rs375706148

chr8-47849499-A-G

Variant summary

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

The NM_006904.7(PRKDC):c.7010T>C(p.Leu2337Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000808 in 1,609,512 control chromosomes in the GnomAD database, including 2 homozygotes. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L2337L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000080 (2 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.7010T>C	p.Leu2337Pro	missense_variant	53/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.7010T>C	p.Leu2337Pro	missense_variant	53/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.7010T>C	p.Leu2337Pro	missense_variant	53/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.7010T>C	p.Leu2337Pro	missense_variant	53/85	1

Frequencies

GnomAD3 genomes AF: 0.0000919 AC: 14 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000820 AC: 20 AN: 243940 Hom.: 0 AF XY: 0.0000982 AC XY: 13 AN XY: 132366

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.000620

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000683

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000449

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000796 AC: 116 AN: 1457132 Hom.: 2 Cov.: 30 AF XY: 0.0000773 AC XY: 56 AN XY: 724700

Gnomad4 AFR exome AF: 0.000392

Gnomad4 AMR exome AF: 0.000162

Gnomad4 ASJ exome AF: 0.000503

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.000183

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152380 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74512

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000576

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

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000662 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe combined immunodeficiency due to DNA-PKcs deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2337 of the PRKDC protein (p.Leu2337Pro). This variant is present in population databases (rs375706148, gnomAD 0.04%). 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: 541988). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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	0.090
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	20
Dann	Benign	0.68
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.0096	T
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
REVEL	Uncertain	0.37
Sift4G	Benign	0.12	T;T
Polyphen		0.027	B;.
Vest4		0.70
MVP		0.83
MPC		0.33
ClinPred		0.029	T
GERP RS		3.9
Varity_R		0.19
gMVP		0.65

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

Other links and lift over

dbSNP: rs375706148; hg19: chr8-48762060;