Phenotypic Mutation 'crackle' (pdf version)
Allele | crackle |
Mutation Type |
critical splice donor site
(2 bp from exon)
|
Chromosome | 16 |
Coordinate | 15,603,914 bp (GRCm39) |
Base Change | T ⇒ C (forward strand) |
Gene |
Prkdc
|
Gene Name | protein kinase, DNA activated, catalytic polypeptide |
Synonym(s) | slip, DNA-PK, XRCC7, DNAPDcs, DOXNPH, dxnph, DNA-PKcs |
Chromosomal Location |
15,455,730-15,660,099 bp (+) (GRCm39)
|
MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PK). It functions with the Ku70/Ku80 heterodimer protein in DNA double strand break repair and recombination. The protein encoded is a member of the PI3/PI4-kinase family.[provided by RefSeq, Jul 2010] PHENOTYPE: Mutations at this locus effect genome stability, radiation sensitivity and DNA repair. Nonsense (scid) and null homozygotes have severe combined immunodeficiency. A BALB/c variant allele reduces enzyme activity and predisposes to breast cancer. [provided by MGI curators]
|
Accession Number | NCBI RefSeq: NM_011159; MGI:104779
|
Mapped | Yes |
Amino Acid Change |
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000023352 †]
† probably from a misspliced transcript
|
AlphaFold |
no structure available at present |
SMART Domains |
Protein: ENSMUSP00000023352 Gene: ENSMUSG00000022672
Domain | Start | End | E-Value | Type |
low complexity region
|
125 |
138 |
N/A |
INTRINSIC |
low complexity region
|
1253 |
1263 |
N/A |
INTRINSIC |
low complexity region
|
1508 |
1522 |
N/A |
INTRINSIC |
NUC194
|
1810 |
2206 |
2.37e-246 |
SMART |
SCOP:d1gw5a_
|
2210 |
2493 |
5e-3 |
SMART |
low complexity region
|
2669 |
2681 |
N/A |
INTRINSIC |
low complexity region
|
2841 |
2855 |
N/A |
INTRINSIC |
Pfam:FAT
|
3024 |
3470 |
8.2e-75 |
PFAM |
PI3Kc
|
3749 |
4068 |
3.67e-86 |
SMART |
FATC
|
4096 |
4128 |
1.57e-9 |
SMART |
|
Predicted Effect |
probably null
|
Meta Mutation Damage Score |
0.9585 |
Is this an essential gene? |
Probably essential (E-score: 0.953) |
Phenotypic Category |
Unknown |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
Alleles Listed at MGI | All Mutations and Alleles(48) : Chemically induced (ENU)(20) Endonuclease-mediated(3) Gene trapped(17) Spontaneous(2) Targeted(5) Transgenic(1)
|
Lab Alleles |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
IGL00157:Prkdc
|
APN |
16 |
15515090 |
missense |
probably damaging |
1.00 |
IGL00225:Prkdc
|
APN |
16 |
15627508 |
missense |
possibly damaging |
0.64 |
IGL00481:Prkdc
|
APN |
16 |
15608330 |
missense |
probably benign |
0.41 |
IGL00488:Prkdc
|
APN |
16 |
15593711 |
splice site |
probably null |
|
IGL00489:Prkdc
|
APN |
16 |
15617790 |
missense |
possibly damaging |
0.51 |
IGL00579:Prkdc
|
APN |
16 |
15482103 |
missense |
probably damaging |
1.00 |
IGL00587:Prkdc
|
APN |
16 |
15470222 |
splice site |
probably benign |
|
IGL00666:Prkdc
|
APN |
16 |
15554699 |
missense |
probably damaging |
1.00 |
IGL00675:Prkdc
|
APN |
16 |
15605022 |
missense |
probably benign |
0.05 |
IGL00708:Prkdc
|
APN |
16 |
15597290 |
missense |
probably damaging |
0.97 |
IGL00725:Prkdc
|
APN |
16 |
15634503 |
missense |
probably benign |
0.10 |
IGL00818:Prkdc
|
APN |
16 |
15577618 |
missense |
possibly damaging |
0.92 |
IGL00917:Prkdc
|
APN |
16 |
15557428 |
missense |
probably damaging |
0.98 |
IGL00990:Prkdc
|
APN |
16 |
15519979 |
missense |
probably benign |
0.03 |
IGL01126:Prkdc
|
APN |
16 |
15487185 |
missense |
probably benign |
0.01 |
IGL01141:Prkdc
|
APN |
16 |
15544568 |
missense |
probably damaging |
0.99 |
IGL01306:Prkdc
|
APN |
16 |
15485595 |
missense |
possibly damaging |
0.67 |
IGL01326:Prkdc
|
APN |
16 |
15647556 |
missense |
probably benign |
|
IGL01335:Prkdc
|
APN |
16 |
15634760 |
critical splice donor site |
probably null |
|
IGL01419:Prkdc
|
APN |
16 |
15653030 |
missense |
probably damaging |
1.00 |
IGL01434:Prkdc
|
APN |
16 |
15531451 |
missense |
probably benign |
0.00 |
IGL01554:Prkdc
|
APN |
16 |
15470166 |
missense |
probably benign |
0.05 |
IGL01671:Prkdc
|
APN |
16 |
15485609 |
missense |
possibly damaging |
0.90 |
IGL01871:Prkdc
|
APN |
16 |
15600951 |
missense |
probably benign |
0.00 |
IGL01874:Prkdc
|
APN |
16 |
15552858 |
missense |
possibly damaging |
0.89 |
IGL01930:Prkdc
|
APN |
16 |
15516751 |
missense |
probably damaging |
1.00 |
IGL01984:Prkdc
|
APN |
16 |
15526643 |
missense |
probably benign |
|
IGL02121:Prkdc
|
APN |
16 |
15535048 |
missense |
probably benign |
0.18 |
IGL02152:Prkdc
|
APN |
16 |
15487149 |
missense |
probably benign |
0.15 |
IGL02172:Prkdc
|
APN |
16 |
15627623 |
missense |
probably benign |
0.10 |
IGL02336:Prkdc
|
APN |
16 |
15603843 |
missense |
probably benign |
0.01 |
IGL02336:Prkdc
|
APN |
16 |
15603842 |
missense |
possibly damaging |
0.47 |
IGL02393:Prkdc
|
APN |
16 |
15634622 |
missense |
probably benign |
0.42 |
IGL02406:Prkdc
|
APN |
16 |
15488399 |
missense |
probably benign |
0.00 |
IGL02500:Prkdc
|
APN |
16 |
15532146 |
critical splice donor site |
probably null |
|
IGL02568:Prkdc
|
APN |
16 |
15544406 |
missense |
probably damaging |
0.98 |
IGL02579:Prkdc
|
APN |
16 |
15488465 |
missense |
possibly damaging |
0.83 |
IGL02652:Prkdc
|
APN |
16 |
15600951 |
missense |
probably benign |
0.00 |
IGL02661:Prkdc
|
APN |
16 |
15587689 |
missense |
possibly damaging |
0.92 |
IGL02685:Prkdc
|
APN |
16 |
15653907 |
missense |
possibly damaging |
0.61 |
IGL02741:Prkdc
|
APN |
16 |
15570590 |
splice site |
probably benign |
|
IGL02803:Prkdc
|
APN |
16 |
15651530 |
splice site |
probably benign |
|
IGL02866:Prkdc
|
APN |
16 |
15649191 |
missense |
probably damaging |
1.00 |
IGL02882:Prkdc
|
APN |
16 |
15469383 |
nonsense |
probably null |
|
IGL02989:Prkdc
|
APN |
16 |
15617880 |
missense |
possibly damaging |
0.67 |
IGL03053:Prkdc
|
APN |
16 |
15652030 |
missense |
probably benign |
0.02 |
IGL03071:Prkdc
|
APN |
16 |
15617848 |
missense |
probably benign |
0.01 |
IGL03091:Prkdc
|
APN |
16 |
15523174 |
splice site |
probably benign |
|
IGL03100:Prkdc
|
APN |
16 |
15531499 |
missense |
probably benign |
0.08 |
IGL03128:Prkdc
|
APN |
16 |
15518608 |
splice site |
probably benign |
|
IGL03168:Prkdc
|
APN |
16 |
15652030 |
missense |
probably benign |
0.02 |
IGL03204:Prkdc
|
APN |
16 |
15587665 |
missense |
probably benign |
0.01 |
IGL03390:Prkdc
|
APN |
16 |
15488490 |
nonsense |
probably null |
|
anhimid
|
UTSW |
16 |
15543325 |
critical splice donor site |
probably null |
|
anhinga
|
UTSW |
16 |
15526796 |
critical splice donor site |
probably null |
|
Bushtit
|
UTSW |
16 |
15570628 |
missense |
probably damaging |
0.97 |
clover
|
UTSW |
16 |
15520020 |
splice site |
probably benign |
|
Daffy
|
UTSW |
16 |
15647561 |
missense |
possibly damaging |
0.86 |
darter
|
UTSW |
16 |
15591477 |
missense |
possibly damaging |
0.93 |
Elmer_fudd
|
UTSW |
16 |
15625922 |
missense |
probably benign |
0.01 |
envenomation
|
UTSW |
16 |
15653091 |
nonsense |
probably null |
|
hobgoblin
|
UTSW |
16 |
15633850 |
missense |
probably damaging |
1.00 |
Incubus
|
UTSW |
16 |
15490191 |
missense |
probably damaging |
1.00 |
liming
|
UTSW |
16 |
15570693 |
nonsense |
probably null |
|
newt
|
UTSW |
16 |
15545590 |
missense |
probably benign |
0.04 |
ornithorhynchus
|
UTSW |
16 |
15634523 |
critical splice donor site |
probably null |
|
primitive
|
UTSW |
16 |
15653022 |
frame shift |
probably null |
|
roadrunner
|
UTSW |
16 |
15651751 |
missense |
probably damaging |
1.00 |
Schreier
|
UTSW |
16 |
15488392 |
missense |
probably benign |
0.00 |
screamer
|
UTSW |
16 |
15649146 |
nonsense |
probably null |
|
Screamer10
|
UTSW |
16 |
15585889 |
missense |
probably damaging |
0.98 |
screamer2
|
UTSW |
16 |
15470416 |
critical splice donor site |
probably null |
|
screamer3
|
UTSW |
16 |
15558196 |
critical splice donor site |
probably null |
|
screamer4
|
UTSW |
16 |
15600943 |
missense |
probably benign |
0.00 |
screamer5
|
UTSW |
16 |
15505268 |
missense |
probably benign |
|
screamer6
|
UTSW |
16 |
15577469 |
missense |
probably damaging |
1.00 |
screamer7
|
UTSW |
16 |
15472681 |
splice site |
probably null |
|
Screamer8
|
UTSW |
16 |
15537297 |
missense |
probably benign |
0.00 |
Screamer9
|
UTSW |
16 |
15552786 |
missense |
probably benign |
0.01 |
Tweetie
|
UTSW |
16 |
15535665 |
missense |
probably damaging |
1.00 |
updock
|
UTSW |
16 |
15612958 |
missense |
probably benign |
|
ANU23:Prkdc
|
UTSW |
16 |
15485595 |
missense |
possibly damaging |
0.67 |
R0008:Prkdc
|
UTSW |
16 |
15526565 |
splice site |
probably benign |
|
R0018:Prkdc
|
UTSW |
16 |
15544406 |
missense |
probably benign |
0.03 |
R0018:Prkdc
|
UTSW |
16 |
15544406 |
missense |
probably benign |
0.03 |
R0069:Prkdc
|
UTSW |
16 |
15544368 |
missense |
probably benign |
0.03 |
R0125:Prkdc
|
UTSW |
16 |
15516871 |
missense |
probably damaging |
0.98 |
R0131:Prkdc
|
UTSW |
16 |
15531517 |
missense |
probably benign |
0.09 |
R0131:Prkdc
|
UTSW |
16 |
15531517 |
missense |
probably benign |
0.09 |
R0132:Prkdc
|
UTSW |
16 |
15531517 |
missense |
probably benign |
0.09 |
R0137:Prkdc
|
UTSW |
16 |
15558196 |
critical splice donor site |
probably null |
|
R0334:Prkdc
|
UTSW |
16 |
15554663 |
missense |
probably benign |
0.00 |
R0373:Prkdc
|
UTSW |
16 |
15609791 |
missense |
probably damaging |
1.00 |
R0485:Prkdc
|
UTSW |
16 |
15651604 |
missense |
probably damaging |
0.97 |
R0511:Prkdc
|
UTSW |
16 |
15649146 |
nonsense |
probably null |
|
R0538:Prkdc
|
UTSW |
16 |
15651652 |
missense |
probably damaging |
1.00 |
R0595:Prkdc
|
UTSW |
16 |
15625952 |
missense |
probably damaging |
1.00 |
R0607:Prkdc
|
UTSW |
16 |
15589921 |
missense |
probably damaging |
0.98 |
R0616:Prkdc
|
UTSW |
16 |
15508271 |
missense |
probably damaging |
1.00 |
R0630:Prkdc
|
UTSW |
16 |
15628665 |
missense |
probably damaging |
1.00 |
R0694:Prkdc
|
UTSW |
16 |
15586501 |
missense |
probably damaging |
1.00 |
R0702:Prkdc
|
UTSW |
16 |
15603835 |
missense |
possibly damaging |
0.95 |
R0965:Prkdc
|
UTSW |
16 |
15647580 |
missense |
probably benign |
|
R1027:Prkdc
|
UTSW |
16 |
15468576 |
missense |
possibly damaging |
0.80 |
R1029:Prkdc
|
UTSW |
16 |
15472613 |
splice site |
probably benign |
|
R1033:Prkdc
|
UTSW |
16 |
15585815 |
missense |
probably damaging |
1.00 |
R1067:Prkdc
|
UTSW |
16 |
15570646 |
missense |
probably damaging |
0.99 |
R1116:Prkdc
|
UTSW |
16 |
15600943 |
missense |
probably benign |
0.00 |
R1187:Prkdc
|
UTSW |
16 |
15577610 |
missense |
probably damaging |
0.98 |
R1226:Prkdc
|
UTSW |
16 |
15491861 |
missense |
possibly damaging |
0.80 |
R1279:Prkdc
|
UTSW |
16 |
15508146 |
missense |
probably damaging |
1.00 |
R1304:Prkdc
|
UTSW |
16 |
15577587 |
missense |
probably damaging |
0.99 |
R1314:Prkdc
|
UTSW |
16 |
15482091 |
missense |
possibly damaging |
0.68 |
R1351:Prkdc
|
UTSW |
16 |
15485564 |
missense |
possibly damaging |
0.62 |
R1509:Prkdc
|
UTSW |
16 |
15549430 |
missense |
probably damaging |
1.00 |
R1512:Prkdc
|
UTSW |
16 |
15505268 |
missense |
probably benign |
|
R1531:Prkdc
|
UTSW |
16 |
15589970 |
missense |
probably benign |
0.01 |
R1579:Prkdc
|
UTSW |
16 |
15493192 |
missense |
probably benign |
0.00 |
R1669:Prkdc
|
UTSW |
16 |
15551922 |
missense |
probably damaging |
1.00 |
R1682:Prkdc
|
UTSW |
16 |
15494853 |
missense |
probably benign |
0.19 |
R1713:Prkdc
|
UTSW |
16 |
15612958 |
missense |
probably benign |
|
R1762:Prkdc
|
UTSW |
16 |
15455825 |
missense |
probably benign |
|
R1789:Prkdc
|
UTSW |
16 |
15557388 |
missense |
probably damaging |
1.00 |
R1822:Prkdc
|
UTSW |
16 |
15577469 |
missense |
probably damaging |
1.00 |
R1848:Prkdc
|
UTSW |
16 |
15625922 |
missense |
probably benign |
0.01 |
R1887:Prkdc
|
UTSW |
16 |
15647499 |
missense |
probably benign |
0.00 |
R1891:Prkdc
|
UTSW |
16 |
15543300 |
missense |
probably benign |
0.02 |
R1921:Prkdc
|
UTSW |
16 |
15532079 |
missense |
possibly damaging |
0.80 |
R1922:Prkdc
|
UTSW |
16 |
15532130 |
missense |
probably benign |
0.00 |
R1929:Prkdc
|
UTSW |
16 |
15472681 |
splice site |
probably null |
|
R1939:Prkdc
|
UTSW |
16 |
15653777 |
missense |
possibly damaging |
0.95 |
R2021:Prkdc
|
UTSW |
16 |
15494873 |
missense |
probably benign |
0.00 |
R2033:Prkdc
|
UTSW |
16 |
15505216 |
splice site |
probably benign |
|
R2056:Prkdc
|
UTSW |
16 |
15545469 |
missense |
probably benign |
0.03 |
R2057:Prkdc
|
UTSW |
16 |
15545469 |
missense |
probably benign |
0.03 |
R2058:Prkdc
|
UTSW |
16 |
15545469 |
missense |
probably benign |
0.03 |
R2082:Prkdc
|
UTSW |
16 |
15533827 |
missense |
probably damaging |
1.00 |
R2109:Prkdc
|
UTSW |
16 |
15505254 |
missense |
probably benign |
0.01 |
R2124:Prkdc
|
UTSW |
16 |
15537297 |
missense |
probably benign |
0.00 |
R2164:Prkdc
|
UTSW |
16 |
15523071 |
missense |
probably damaging |
1.00 |
R2174:Prkdc
|
UTSW |
16 |
15552786 |
missense |
probably benign |
0.01 |
R2191:Prkdc
|
UTSW |
16 |
15516688 |
missense |
probably damaging |
1.00 |
R2270:Prkdc
|
UTSW |
16 |
15472681 |
splice site |
probably null |
|
R2271:Prkdc
|
UTSW |
16 |
15472681 |
splice site |
probably null |
|
R2272:Prkdc
|
UTSW |
16 |
15472681 |
splice site |
probably null |
|
R2356:Prkdc
|
UTSW |
16 |
15502068 |
missense |
probably benign |
|
R2852:Prkdc
|
UTSW |
16 |
15470416 |
critical splice donor site |
probably null |
|
R3115:Prkdc
|
UTSW |
16 |
15482222 |
missense |
probably benign |
0.01 |
R3116:Prkdc
|
UTSW |
16 |
15482222 |
missense |
probably benign |
0.01 |
R3499:Prkdc
|
UTSW |
16 |
15585889 |
missense |
probably damaging |
0.98 |
R3687:Prkdc
|
UTSW |
16 |
15617831 |
missense |
probably benign |
|
R3834:Prkdc
|
UTSW |
16 |
15609810 |
missense |
probably damaging |
1.00 |
R3835:Prkdc
|
UTSW |
16 |
15609810 |
missense |
probably damaging |
1.00 |
R3961:Prkdc
|
UTSW |
16 |
15647475 |
splice site |
probably null |
|
R4151:Prkdc
|
UTSW |
16 |
15634637 |
missense |
probably benign |
|
R4233:Prkdc
|
UTSW |
16 |
15653783 |
missense |
probably benign |
0.11 |
R4281:Prkdc
|
UTSW |
16 |
15623963 |
splice site |
probably null |
|
R4296:Prkdc
|
UTSW |
16 |
15555769 |
missense |
probably damaging |
0.99 |
R4344:Prkdc
|
UTSW |
16 |
15585886 |
missense |
probably damaging |
0.98 |
R4424:Prkdc
|
UTSW |
16 |
15653946 |
missense |
probably damaging |
1.00 |
R4424:Prkdc
|
UTSW |
16 |
15591603 |
missense |
probably damaging |
0.98 |
R4497:Prkdc
|
UTSW |
16 |
15518517 |
missense |
probably benign |
0.43 |
R4549:Prkdc
|
UTSW |
16 |
15554734 |
missense |
possibly damaging |
0.89 |
R4594:Prkdc
|
UTSW |
16 |
15585830 |
missense |
possibly damaging |
0.64 |
R4603:Prkdc
|
UTSW |
16 |
15628688 |
missense |
probably damaging |
0.98 |
R4615:Prkdc
|
UTSW |
16 |
15480938 |
missense |
probably damaging |
0.99 |
R4648:Prkdc
|
UTSW |
16 |
15634638 |
missense |
probably benign |
0.05 |
R4662:Prkdc
|
UTSW |
16 |
15551916 |
missense |
probably damaging |
1.00 |
R4680:Prkdc
|
UTSW |
16 |
15589894 |
missense |
probably benign |
0.00 |
R4700:Prkdc
|
UTSW |
16 |
15519976 |
missense |
probably damaging |
1.00 |
R4716:Prkdc
|
UTSW |
16 |
15628701 |
missense |
probably benign |
0.32 |
R4720:Prkdc
|
UTSW |
16 |
15485579 |
missense |
probably benign |
|
R4785:Prkdc
|
UTSW |
16 |
15466840 |
missense |
probably benign |
0.21 |
R4822:Prkdc
|
UTSW |
16 |
15468576 |
missense |
possibly damaging |
0.80 |
R4829:Prkdc
|
UTSW |
16 |
15519939 |
missense |
possibly damaging |
0.80 |
R4981:Prkdc
|
UTSW |
16 |
15496173 |
missense |
probably damaging |
1.00 |
R4989:Prkdc
|
UTSW |
16 |
15491861 |
missense |
possibly damaging |
0.80 |
R5059:Prkdc
|
UTSW |
16 |
15655882 |
missense |
probably damaging |
1.00 |
R5074:Prkdc
|
UTSW |
16 |
15589912 |
missense |
probably damaging |
1.00 |
R5115:Prkdc
|
UTSW |
16 |
15608444 |
missense |
probably benign |
|
R5151:Prkdc
|
UTSW |
16 |
15533899 |
missense |
probably damaging |
1.00 |
R5165:Prkdc
|
UTSW |
16 |
15496136 |
missense |
probably damaging |
1.00 |
R5215:Prkdc
|
UTSW |
16 |
15589985 |
missense |
possibly damaging |
0.64 |
R5270:Prkdc
|
UTSW |
16 |
15552819 |
missense |
probably damaging |
1.00 |
R5278:Prkdc
|
UTSW |
16 |
15532838 |
missense |
probably damaging |
1.00 |
R5351:Prkdc
|
UTSW |
16 |
15649176 |
missense |
probably benign |
0.03 |
R5416:Prkdc
|
UTSW |
16 |
15623814 |
missense |
probably damaging |
1.00 |
R5418:Prkdc
|
UTSW |
16 |
15612961 |
missense |
probably benign |
0.20 |
R5437:Prkdc
|
UTSW |
16 |
15587739 |
missense |
possibly damaging |
0.46 |
R5452:Prkdc
|
UTSW |
16 |
15586501 |
missense |
possibly damaging |
0.96 |
R5518:Prkdc
|
UTSW |
16 |
15496172 |
missense |
probably damaging |
1.00 |
R5538:Prkdc
|
UTSW |
16 |
15469333 |
missense |
probably damaging |
1.00 |
R5589:Prkdc
|
UTSW |
16 |
15524655 |
missense |
probably benign |
0.02 |
R5618:Prkdc
|
UTSW |
16 |
15627476 |
missense |
probably damaging |
1.00 |
R5640:Prkdc
|
UTSW |
16 |
15647633 |
missense |
possibly damaging |
0.86 |
R5661:Prkdc
|
UTSW |
16 |
15628634 |
missense |
possibly damaging |
0.81 |
R5771:Prkdc
|
UTSW |
16 |
15482097 |
missense |
probably damaging |
1.00 |
R5772:Prkdc
|
UTSW |
16 |
15597252 |
missense |
possibly damaging |
0.49 |
R5783:Prkdc
|
UTSW |
16 |
15535665 |
missense |
probably damaging |
1.00 |
R5792:Prkdc
|
UTSW |
16 |
15634616 |
missense |
probably damaging |
1.00 |
R5797:Prkdc
|
UTSW |
16 |
15555698 |
nonsense |
probably null |
|
R5826:Prkdc
|
UTSW |
16 |
15551962 |
missense |
probably benign |
|
R5883:Prkdc
|
UTSW |
16 |
15533778 |
missense |
probably benign |
|
R5895:Prkdc
|
UTSW |
16 |
15570693 |
nonsense |
probably null |
|
R5998:Prkdc
|
UTSW |
16 |
15601021 |
missense |
probably damaging |
1.00 |
R6000:Prkdc
|
UTSW |
16 |
15647561 |
missense |
possibly damaging |
0.86 |
R6120:Prkdc
|
UTSW |
16 |
15557335 |
missense |
probably benign |
0.00 |
R6145:Prkdc
|
UTSW |
16 |
15589937 |
missense |
probably damaging |
1.00 |
R6209:Prkdc
|
UTSW |
16 |
15608456 |
missense |
probably damaging |
1.00 |
R6293:Prkdc
|
UTSW |
16 |
15605019 |
missense |
probably benign |
0.00 |
R6321:Prkdc
|
UTSW |
16 |
15532783 |
missense |
probably benign |
|
R6376:Prkdc
|
UTSW |
16 |
15587749 |
missense |
probably benign |
0.06 |
R6387:Prkdc
|
UTSW |
16 |
15516679 |
missense |
probably benign |
0.01 |
R6406:Prkdc
|
UTSW |
16 |
15535665 |
missense |
probably damaging |
1.00 |
R6469:Prkdc
|
UTSW |
16 |
15612939 |
missense |
probably benign |
0.10 |
R6486:Prkdc
|
UTSW |
16 |
15570628 |
missense |
probably damaging |
0.97 |
R6665:Prkdc
|
UTSW |
16 |
15603914 |
critical splice donor site |
probably null |
|
R6703:Prkdc
|
UTSW |
16 |
15488392 |
missense |
probably benign |
0.00 |
R6774:Prkdc
|
UTSW |
16 |
15543325 |
critical splice donor site |
probably null |
|
R6854:Prkdc
|
UTSW |
16 |
15469402 |
missense |
probably damaging |
1.00 |
R6878:Prkdc
|
UTSW |
16 |
15594936 |
missense |
probably benign |
0.31 |
R6882:Prkdc
|
UTSW |
16 |
15626020 |
missense |
probably benign |
0.33 |
R6882:Prkdc
|
UTSW |
16 |
15601127 |
critical splice donor site |
probably null |
|
R6949:Prkdc
|
UTSW |
16 |
15617853 |
missense |
probably benign |
|
R6950:Prkdc
|
UTSW |
16 |
15633850 |
missense |
probably damaging |
1.00 |
R7019:Prkdc
|
UTSW |
16 |
15587830 |
missense |
probably benign |
0.00 |
R7064:Prkdc
|
UTSW |
16 |
15608317 |
missense |
probably benign |
0.00 |
R7097:Prkdc
|
UTSW |
16 |
15507207 |
missense |
probably damaging |
1.00 |
R7201:Prkdc
|
UTSW |
16 |
15516667 |
missense |
probably benign |
0.12 |
R7235:Prkdc
|
UTSW |
16 |
15532127 |
missense |
probably benign |
|
R7283:Prkdc
|
UTSW |
16 |
15535628 |
missense |
probably benign |
0.00 |
R7401:Prkdc
|
UTSW |
16 |
15466602 |
missense |
probably damaging |
1.00 |
R7525:Prkdc
|
UTSW |
16 |
15490191 |
missense |
probably damaging |
1.00 |
R7647:Prkdc
|
UTSW |
16 |
15555807 |
missense |
probably damaging |
1.00 |
R7679:Prkdc
|
UTSW |
16 |
15649183 |
missense |
probably damaging |
1.00 |
R7803:Prkdc
|
UTSW |
16 |
15623960 |
missense |
probably null |
0.05 |
R7858:Prkdc
|
UTSW |
16 |
15507141 |
missense |
probably benign |
0.11 |
R7872:Prkdc
|
UTSW |
16 |
15532870 |
missense |
probably benign |
0.05 |
R7896:Prkdc
|
UTSW |
16 |
15526767 |
missense |
probably damaging |
0.97 |
R8032:Prkdc
|
UTSW |
16 |
15597315 |
missense |
probably benign |
0.00 |
R8055:Prkdc
|
UTSW |
16 |
15634749 |
missense |
probably benign |
0.09 |
R8153:Prkdc
|
UTSW |
16 |
15482108 |
missense |
probably damaging |
1.00 |
R8281:Prkdc
|
UTSW |
16 |
15523117 |
missense |
probably damaging |
1.00 |
R8302:Prkdc
|
UTSW |
16 |
15653946 |
missense |
probably damaging |
1.00 |
R8322:Prkdc
|
UTSW |
16 |
15532005 |
splice site |
probably benign |
|
R8401:Prkdc
|
UTSW |
16 |
15591477 |
missense |
possibly damaging |
0.93 |
R8440:Prkdc
|
UTSW |
16 |
15653022 |
frame shift |
probably null |
|
R8458:Prkdc
|
UTSW |
16 |
15608540 |
critical splice donor site |
probably null |
|
R8472:Prkdc
|
UTSW |
16 |
15469400 |
missense |
probably damaging |
1.00 |
R8478:Prkdc
|
UTSW |
16 |
15466788 |
missense |
probably benign |
0.00 |
R8515:Prkdc
|
UTSW |
16 |
15482232 |
missense |
probably damaging |
1.00 |
R8546:Prkdc
|
UTSW |
16 |
15480899 |
missense |
probably damaging |
1.00 |
R8678:Prkdc
|
UTSW |
16 |
15526796 |
critical splice donor site |
probably null |
|
R8739:Prkdc
|
UTSW |
16 |
15626068 |
missense |
probably benign |
0.01 |
R8749:Prkdc
|
UTSW |
16 |
15601029 |
missense |
possibly damaging |
0.85 |
R8836:Prkdc
|
UTSW |
16 |
15545523 |
missense |
probably damaging |
1.00 |
R8904:Prkdc
|
UTSW |
16 |
15545590 |
missense |
probably benign |
0.04 |
R8952:Prkdc
|
UTSW |
16 |
15491624 |
intron |
probably benign |
|
R8971:Prkdc
|
UTSW |
16 |
15493229 |
missense |
probably null |
0.99 |
R8974:Prkdc
|
UTSW |
16 |
15617726 |
splice site |
probably null |
|
R9052:Prkdc
|
UTSW |
16 |
15508160 |
missense |
probably benign |
0.05 |
R9069:Prkdc
|
UTSW |
16 |
15653091 |
nonsense |
probably null |
|
R9200:Prkdc
|
UTSW |
16 |
15523153 |
missense |
probably damaging |
1.00 |
R9235:Prkdc
|
UTSW |
16 |
15651751 |
missense |
probably damaging |
1.00 |
R9278:Prkdc
|
UTSW |
16 |
15634523 |
critical splice donor site |
probably null |
|
R9309:Prkdc
|
UTSW |
16 |
15526792 |
nonsense |
probably null |
|
R9386:Prkdc
|
UTSW |
16 |
15496136 |
missense |
probably damaging |
0.99 |
R9452:Prkdc
|
UTSW |
16 |
15485465 |
missense |
possibly damaging |
0.90 |
R9500:Prkdc
|
UTSW |
16 |
15657079 |
missense |
possibly damaging |
0.76 |
R9608:Prkdc
|
UTSW |
16 |
15548335 |
missense |
probably damaging |
1.00 |
R9608:Prkdc
|
UTSW |
16 |
15548334 |
missense |
possibly damaging |
0.96 |
R9636:Prkdc
|
UTSW |
16 |
15548341 |
missense |
probably benign |
0.19 |
R9656:Prkdc
|
UTSW |
16 |
15617818 |
missense |
probably benign |
0.00 |
R9674:Prkdc
|
UTSW |
16 |
15533819 |
missense |
probably damaging |
0.98 |
R9760:Prkdc
|
UTSW |
16 |
15657044 |
nonsense |
probably null |
|
X0023:Prkdc
|
UTSW |
16 |
15558142 |
missense |
probably benign |
|
Z1176:Prkdc
|
UTSW |
16 |
15505286 |
nonsense |
probably null |
|
|
Mode of Inheritance |
Unknown |
Local Stock | |
Repository | |
Last Updated |
2019-09-04 9:26 PM
by Diantha La Vine
|
Record Created |
2019-04-11 11:13 AM
by Bruce Beutler
|
Record Posted |
2019-04-19 |
Phenotypic Description |
The crackle phenotype was identified among G3 mice of the pedigree R6665, some of which showed increased B to T cell ratios (Figure 1) and increased CD4 to CD8 T cell ratios (Figure 2) as well as reduced frequencies of B cells (Figure 3), B1 cells (Figure 4), T cells (Figure 5), CD4+ T cells (Figure 6), CD8+ T cells (Figure 7), naïve CD4 T cells in CD4 T cells (Figure 8), and naïve CD8 T cells in CD8 T cells (Figure 9) with concomitant increased frequencies of central memory CD4 T cells in CD4 T cells (Figure 10), central memory CD8 T cells in CD8 T cells (Figure 11), effector memory CD4 T cells in CD4 T cells (Figure 12), effector memory CD8 T cells in CD8 T cells (Figure 13), and NK cells (Figure 14), all in the peripheral blood. The mice also showed reduced B220 expression on peripheral blood B cells (Figure 15). Expression of CD44 was increased on peripheral blood T cells (Figure 16), CD4+ T cells (Figure 17), and CD8+ T cells (Figure 18).
|
Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 35 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Prkdc: a T to C transition at base pair 15,786,050 (v38) on chromosome 16, or base pair 148,608 in the GenBank genomic region NC_000082 within the splice donor site of intron 64 (2-base pairs from exon 64 [out of 86 total exons]). The strongest association was found with a recessive model of inheritance to the CD44+ CD4 mean fluorescence intensity (MFI) phenotype, wherein four variant homozygotes departed phenotypically from 21 homozygous reference mice and 30 heterozygous mice with a P value of 3.124 x 10-39 (Figure 19).
The effect of the mutation at the cDNA and protein levels has not been examined, but the mutation is predicted to result in the use of a cryptic site in exon 64, which would cause an 89-base pair deletion in exon 64. The resulting protein product would have a frame-shift beginning after amino acid 2,946 (the protein is normally 4,128 amino acids in length) and termination after the inclusion of two aberrant amino acids.
<--exon 63 exon 64--> intron 64--> exon 65-->
8799 ……GAACTTGCTAA ACTCTATCGTTCG……GTGAGTTAGGAA……TTGTATGATGAG gtaaaatcaatctctggca…… GCTTTAAATAA……
2926 ……-E--L--A--K --L--Y--R--S-……-------------------------- S--F--K--*-
correct deleted aberrrant
|
The donor splice site of intron 64, which is destroyed by the crackle mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
|
Illustration of Mutations in
Gene & Protein |
|
---|
Protein Prediction |
The 12,674 base pair Prkdc transcript encodes the 4,128 amino acid, 471 kDa catalytic subunit of the DNA-PK complex, DNA-PKCS. DNA-PKCS is a serine/threonine kinase and member of the phosphatidylinositol 3-kinase-like kinases (PIKK) family (see worker) [reviewed in (1)]. DNA-PKCS has several domains that are essential for its function (Figure 20). A leucine rich region (LRR, aa 1501-1536) mediates the association of DNA-PKCS with C1D, a DNA-binding nuclear matrix-associated factor. The LRR facilitates the intrinsic binding of DNA-PKCS to DNA (2). The DNA-PKCS protein also contains three tetratricopeptide repeats (TPR) (aa 1720-1753, 2921-2954, 2956-2983) that are proposed to assist in protein-protein interactions. A 380 amino acid region at the C terminus constitutes the catalytic domain, designated the PIKK domain, of DNA-PKCS (aa 3747-4015) (3). The PIKK domain is flanked by the FAT domain (named for its homology to FRAP, ATM and TRRAP, aa 2884-3539) and a FATC domain (FAT at the extreme C-terminus, aa 4096-4128) (3). The FAT and FATC domains occur in combination in all PIKK family members. The C-terminal region containing the FATC domain is essential for the kinase activity of DNA-PKCS (4-6). The N-terminal portion of the protein up to the FAT domain consists of HEAT (Huntingtin, Elongation factor 3, A subunit of protein phosphatase 2A and TOR1) repeats (amino acids 288-323, 1001-1037, and 1050-1086) (7). HEAT repeats are helical structural repeats that mediate protein-protein interactions (8). The crackle mutation is predicted to result in a frame-shifted protein product beginning after amino acid 2,946 of the protein and termination after the inclusion of two aberrant amino acids. Please see the record clover for information about Prkdc.
|
Putative Mechanism | DNA-PKCS is the catalytic subunit of the DNA-PK complex and is essential for DNA double-strand break repair during nonhomologous end joining (NHEJ) and during the assembly of immune receptor genes (i.e., V(D)J recombination) in developing lymphocytes. Mutations in Prkdc are linked to severe combined immunodeficiency (SCID) in several animal models, a condition marked by lymphopenia, hypogammaglobulinemia, and impaired T and B cell-mediated functions (e.g. defective V(D)J recombination and reduced numbers of peripheral lymphocytes) (9-11). Mutations in Prkdc also exhibit uncapped telomeres and a large number of telomeric fusions, leading to genomic instability (9;12;13). In a spontaneous mouse model of SCID, a DNA-PKCS point mutation resulting in the loss of 83 C-terminal amino acids, a reduction in protein expression, and a block in lymphocyte development has been identified (14). The phenotype in the crackle mice indicate a loss of DNA-PKCS-associated function.
|
Primers |
PCR Primer
crackle_pcr_F: GTGACTCACTTACCACCTAGC
crackle_pcr_R: AAGGCTTTGTCTCCTTTCAATG
Sequencing Primer
crackle_seq_F: TGCATATTAAAACAACTTGGGGC
crackle_seq_R: CCTTTCAATGTTGTCTTAAAAAGAGC
|
Genotyping | PCR program 1) 94°C 2:00 2) 94°C 0:30 3) 55°C 0:30 4) 72°C 1:00 5) repeat steps (2-4) 40x 6) 72°C 10:00 7) 4°C hold
The following sequence of 528 nucleotides is amplified (chromosome 16, + strand):
1 gtgactcact taccacctag ctttctatat tttgttttca aatgcatatt aaaacaactt 61 ggggctaaag aagtaaaacc taaaggaaat ttcagaacca ttaaatttta tatttccaac 121 aaaatactac ttatatgtta tctgcgtgaa atcttctttc aatattaatg aaaattgtgt 181 aaatacttct atttggtgat ctgaactttg tttttcagac tctatcgttc gattggggag 241 tatgatgttc tccgtggcat ttttagcagt gagttaggaa caacgcagga cactcagaac 301 gcactattag cagaagctag aagtgattat tgtcaagctg ctaagttgta tgatgaggta 361 aaatcaatct ctggcaaata tatcagctac ttaaccacct cggctctgta catgttaaaa 421 agaactgtta gctttagtgt tagatgtgtt tttataataa ccacttgtga catcattgtt 481 attgtatctt gctcttttta agacaacatt gaaaggagac aaagcctt
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red. |
References |
3. Rivera-Calzada, A., Maman, J. D., Spagnolo, L., Pearl, L. H., and Llorca, O. (2005) Three-Dimensional Structure and Regulation of the DNA-Dependent Protein Kinase Catalytic Subunit (DNA-PKcs). Structure. 13, 243-255.
4. Jiang, X., Sun, Y., Chen, S., Roy, K., and Price, B. D. (2006) The FATC Domains of PIKK Proteins are Functionally Equivalent and Participate in the Tip60-Dependent Activation of DNA-PKcs and ATM. J Biol Chem. 281, 15741-15746.
5. Beamish, H. J., Jessberger, R., Riballo, E., Priestley, A., Blunt, T., Kysela, B., and Jeggo, P. A. (2000) The C-Terminal Conserved Domain of DNA-PKcs, Missing in the SCID Mouse, is Required for Kinase Activity. Nucleic Acids Res. 28, 1506-1513.
6. Priestley, A., Beamish, H. J., Gell, D., Amatucci, A. G., Muhlmann-Diaz, M. C., Singleton, B. K., Smith, G. C., Blunt, T., Schalkwyk, L. C., Bedford, J. S., Jackson, S. P., Jeggo, P. A., and Taccioli, G. E. (1998) Molecular and Biochemical Characterisation of DNA-Dependent Protein Kinase-Defective Rodent Mutant Irs-20. Nucleic Acids Res. 26, 1965-1973.
12. Espejel, S., Franco, S., Sgura, A., Gae, D., Bailey, S. M., Taccioli, G. E., and Blasco, M. A. (2002) Functional Interaction between DNA-PKcs and Telomerase in Telomere Length Maintenance. EMBO J. 21, 6275-6287.
13. Williams, E. S., Klingler, R., Ponnaiya, B., Hardt, T., Schrock, E., Lees-Miller, S. P., Meek, K., Ullrich, R. L., and Bailey, S. M. (2009) Telomere Dysfunction and DNA-PKcs Deficiency: Characterization and Consequence. Cancer Res. 69, 2100-2107.
14. Danska, J. S., Holland, D. P., Mariathasan, S., Williams, K. M., and Guidos, C. J. (1996) Biochemical and Genetic Defects in the DNA-Dependent Protein Kinase in Murine Scid Lymphocytes. Mol Cell Biol. 16, 5507-5517.
|
Science Writers | Anne Murray |
Illustrators | Diantha La Vine |
Authors | Xue Zhong, Jin Huk Choi, and Bruce Beutler |