7-152649052-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005431.2(XRCC2):c.433C>G(p.Leu145Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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. L145F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: XRCC2 NM_005431.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.09

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14421421).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC2	NM_005431.2	c.433C>G	p.Leu145Val	missense_variant	3/3	ENST00000359321.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC2	ENST00000359321.2	c.433C>G	p.Leu145Val	missense_variant	3/3	1	NM_005431.2	P1
XRCC2	ENST00000495707.1	n.455C>G		non_coding_transcript_exon_variant	3/3	1
XRCC2	ENST00000698506.1	c.265C>G	p.Leu89Val	missense_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 09, 2016	In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a XRCC2-related disease. This sequence change replaces leucine with valine at codon 145 of the XRCC2 protein (p.Leu145Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2015	This variant is denoted XRCC2 c.433C>G at the cDNA level, p.Leu145Val (L145V) at the protein level, and results in the change of a Leucine to a Valine (CTT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. XRCC2 Leu145Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. XRCC2 Leu145Val occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located in the Walker B ATP binding motif (Miller 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether XRCC2 Leu145Val is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	17
Dann	Benign	0.95
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.079
Sift	Benign	0.48	T
Sift4G	Benign	0.31	T
Polyphen		0.013	B
Vest4		0.18
MutPred		0.58		Loss of stability (P = 0.2857);
MVP		0.35
MPC		0.042
ClinPred		0.25	T
GERP RS		3.4
Varity_R		0.12
gMVP		0.46

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: rs1060502669; hg19: chr7-152346137;