NM_006904.7:c.2629G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006904.7(PRKDC):​c.2629G>C​(p.Asp877His) variant causes a missense change. The variant allele was found at a frequency of 0.0000532 in 1,521,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D877E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

PRKDC
NM_006904.7 missense

Scores

1
6
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.58
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07185808).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRKDCNM_006904.7 linkc.2629G>C p.Asp877His missense_variant Exon 24 of 86 ENST00000314191.7 NP_008835.5 P78527-1
PRKDCNM_001081640.2 linkc.2629G>C p.Asp877His missense_variant Exon 24 of 85 NP_001075109.1 P78527-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRKDCENST00000314191.7 linkc.2629G>C p.Asp877His missense_variant Exon 24 of 86 1 NM_006904.7 ENSP00000313420.3 P78527-1
PRKDCENST00000338368.7 linkc.2629G>C p.Asp877His missense_variant Exon 24 of 85 1 ENSP00000345182.4 P78527-2

Frequencies

GnomAD3 genomes
AF:
0.000276
AC:
42
AN:
152208
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000892
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:
0.0000147
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.0000344
AC:
7
AN:
203348
Hom.:
0
AF XY:
0.0000180
AC XY:
2
AN XY:
111392
show subpopulations
Gnomad AFR exome
AF:
0.000447
Gnomad AMR exome
AF:
0.0000475
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000285
AC:
39
AN:
1369538
Hom.:
0
Cov.:
30
AF XY:
0.0000163
AC XY:
11
AN XY:
675866
show subpopulations
Gnomad4 AFR exome
AF:
0.00106
Gnomad4 AMR exome
AF:
0.0000640
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:
0.0000891
GnomAD4 genome
AF:
0.000276
AC:
42
AN:
152326
Hom.:
0
Cov.:
32
AF XY:
0.000282
AC XY:
21
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.000890
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:
0.0000147
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.000141
Hom.:
0
Bravo
AF:
0.000257
ESP6500AA
AF:
0.00104
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000414
AC:
5

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 09, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2629G>C (p.D877H) alteration is located in exon 24 (coding exon 24) of the PRKDC gene. This alteration results from a G to C substitution at nucleotide position 2629, causing the aspartic acid (D) at amino acid position 877 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Severe combined immunodeficiency due to DNA-PKcs deficiency Uncertain:1
Dec 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 877 of the PRKDC protein (p.Asp877His). This variant is present in population databases (rs200560953, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with PRKDC-related conditions. ClinVar contains an entry for this variant (Variation ID: 475224). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PRKDC protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
22
DANN
Uncertain
0.97
DEOGEN2
Benign
0.16
T;.
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.072
T;T
MetaSVM
Benign
-1.1
T
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.6
N;N
REVEL
Benign
0.044
Sift
Uncertain
0.025
D;D
Sift4G
Uncertain
0.0070
D;D
Polyphen
0.83
P;P
Vest4
0.38
MVP
0.37
MPC
0.51
ClinPred
0.27
T
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.14
gMVP
0.20

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: rs200560953; hg19: chr8-48826613; API