rs374403400

chr8-47849230-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_006904.7(PRKDC):c.7204C>T(p.Leu2402Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000827 in 1,613,960 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (2 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.48

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015803784).
• BP6: Variant 8-47849230-G-A is Benign according to our data. Variant chr8-47849230-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440192.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.7204C>T	p.Leu2402Phe	missense_variant	54/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.7204C>T	p.Leu2402Phe	missense_variant	54/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.7204C>T	p.Leu2402Phe	missense_variant	54/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.7204C>T	p.Leu2402Phe	missense_variant	54/85	1

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000602 AC: 150 AN: 249276 Hom.: 0 AF XY: 0.000666 AC XY: 90 AN XY: 135234

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.000789

Gnomad NFE exome AF: 0.000681

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000858 AC: 1254 AN: 1461710 Hom.: 2 Cov.: 31 AF XY: 0.000861 AC XY: 626 AN XY: 727138

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.000925

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000604 AC XY: 45 AN XY: 74442

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000951 Hom.: 0

Bravo AF: 0.000491

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000602 AC: 5

ExAC AF: 0.000637 AC: 77

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 08, 2022	Variant summary: PRKDC c.7201C>T (p.Leu2401Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0006 in 249276 control chromosomes (gnomAD). This variant is also known as refseq c.7204C>T (p.Leu2402Phe). The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRKDC causing Severe Combined Immunodeficiency phenotype (0.00035), strongly suggesting that the variant is benign. c.7201C>T has been reported in the literature in an individual affected with colorectal cancer (Kayser_2018). This report does not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency (specifically Immunodeficiency 26, with or without neurologic abnormalities). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 06, 2016	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2022

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2402 of the PRKDC protein (p.Leu2402Phe). This variant is present in population databases (rs374403400, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 440192). 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. 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

PRKDC: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.47	T
REVEL	Benign	0.14
Sift4G	Uncertain	0.022	D;D
Polyphen		0.96	P;.
Vest4		0.30
MVP		0.55
MPC		0.24
ClinPred		0.034	T
GERP RS		3.9
Varity_R		0.091
gMVP		0.30

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: rs374403400; hg19: chr8-48761791;