8-47774268-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006904.7(PRKDC):​c.12292C>A​(p.Leu4098Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,609,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PRKDC
NM_006904.7 missense

Scores

7
4
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.51
Variant links:
Genes affected
PRKDC (HGNC:9413): (protein kinase, DNA-activated, catalytic subunit) 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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRKDCNM_006904.7 linkc.12292C>A p.Leu4098Ile missense_variant Exon 86 of 86 ENST00000314191.7 NP_008835.5 P78527-1
PRKDCNM_001081640.2 linkc.12199C>A p.Leu4067Ile missense_variant Exon 85 of 85 NP_001075109.1 P78527-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRKDCENST00000314191.7 linkc.12292C>A p.Leu4098Ile missense_variant Exon 86 of 86 1 NM_006904.7 ENSP00000313420.3 P78527-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1457718
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
724546
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Severe combined immunodeficiency due to DNA-PKcs deficiency Uncertain:1
Dec 27, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces leucine with isoleucine at codon 4098 of the PRKDC protein (p.Leu4098Ile). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and isoleucine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PRKDC-related disease. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Uncertain
0.014
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.30
T;.
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.86
D;D
M_CAP
Benign
0.083
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Pathogenic
3.2
M;.
PrimateAI
Benign
0.45
T
REVEL
Uncertain
0.59
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.98
D;.
Vest4
0.64
MutPred
0.76
Loss of disorder (P = 0.1544);.;
MVP
0.66
MPC
0.72
ClinPred
0.98
D
GERP RS
5.6
Varity_R
0.47
gMVP
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1323956173; hg19: chr8-48686829; API