chr7-152648818-A-T

Variant names:

• chr7-152648818-A-T
• NM_005431.2:c.667T>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005431.2(XRCC2):​c.667T>A​(p.Tyr223Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: XRCC2 NM_005431.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.39

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC2	NM_005431.2	c.667T>A	p.Tyr223Asn	missense_variant	Exon 3 of 3	ENST00000359321.2	NP_005422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC2	ENST00000359321.2	c.667T>A	p.Tyr223Asn	missense_variant	Exon 3 of 3	1	NM_005431.2	ENSP00000352271.1
XRCC2	ENST00000495707.1	n.689T>A		non_coding_transcript_exon_variant	Exon 3 of 3	1
XRCC2	ENST00000698506.1	c.499T>A	p.Tyr167Asn	missense_variant	Exon 2 of 2			ENSP00000513758.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 223 of the XRCC2 protein (p.Tyr223Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with XRCC2-related conditions. 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. 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	0.24
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Benign	0.59
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.40	B
Vest4		0.82
MutPred		0.54		Gain of disorder (P = 0.0376);
MVP		0.47
MPC		0.32
ClinPred		0.80	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-152345903;