7-152648660-A-C

Variant summary

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

The NM_005431.2(XRCC2):c.825T>G(p.Ser275Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000362 in 1,603,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. S275S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

XRCC2
NM_005431.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.428

Variant links:

Genes affected

XRCC2 (HGNC:12829): (X-ray repair cross complementing 2) This gene encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage. This gene is involved in the repair of DNA double-strand breaks by homologous recombination and it functionally complements Chinese hamster irs1, a repair-deficient mutant that exhibits hypersensitivity to a number of different DNA-damaging agents. [provided by RefSeq, Jul 2008]

XRCC2 links:

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=0.10213509).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC2	NM_005431.2 linkuse as main transcript	c.825T>G	p.Ser275Arg	missense_variant	3/3	ENST00000359321.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
XRCC2	ENST00000359321.2 linkuse as main transcript	c.825T>G	p.Ser275Arg	missense_variant	3/3	1	NM_005431.2	P1
XRCC2	ENST00000495707.1 linkuse as main transcript	n.847T>G		non_coding_transcript_exon_variant	3/3	1
XRCC2	ENST00000698506.1 linkuse as main transcript	c.657T>G	p.Ser219Arg	missense_variant	2/2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000909

AC:

AN:

242012

Hom.:

AF XY:

0.0000991

AC XY:

AN XY:

131224

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000829

Gnomad NFE exome

AF:

0.0000362

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.0000344

AC:

AN:

1451522

Hom.:

Cov.:

AF XY:

0.0000402

AC XY:

AN XY:

721654

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.000708

Gnomad4 NFE exome

AF:

0.00000722

Gnomad4 OTH exome

AF:

0.0000834

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 31, 2023

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. 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 XRCC2 protein function. ClinVar contains an entry for this variant (Variation ID: 827540). This variant has not been reported in the literature in individuals affected with XRCC2-related conditions. This variant is present in population databases (rs770438650, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 275 of the XRCC2 protein (p.Ser275Arg). -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2023

The p.S275R variant (also known as c.825T>G), located in coding exon 3 of the XRCC2 gene, results from a T to G substitution at nucleotide position 825. The serine at codon 275 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.29

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.63

M_CAP

Benign

0.025

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

0.85

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.5

REVEL

Benign

0.11

Sift

Benign

0.061

Sift4G

Benign

0.29

Polyphen

0.67

Vest4

0.21

MutPred

0.30

Gain of MoRF binding (P = 0.0668);

MVP

0.65

MPC

0.097

ClinPred

0.068

GERP RS

1.5

Varity_R

0.11

gMVP

0.26

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over