NM_005431.2:c.563G>A

Variant names:

• chr7-152648922-C-T
• rs3218536
• NM_005431.2:c.563G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005431.2(XRCC2):​c.563G>A​(p.Arg188His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0748 in 1,614,060 control chromosomes in the GnomAD database, including 5,145 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R188P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.055 (336 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4809 hom.)
• Consequence: XRCC2 NM_005431.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.57
• Publications: 215 publications found

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 Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group U

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• premature ovarian failure 17

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• spermatogenic failure 50

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000298894 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021595955).
• BP6: Variant 7-152648922-C-T is Benign according to our data. Variant chr7-152648922-C-T is described in ClinVar as Benign. ClinVar VariationId is 486723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005431.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC2	NM_005431.2	MANE Select	c.563G>A	p.Arg188His	missense	Exon 3 of 3	NP_005422.1	O43543

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC2	ENST00000359321.2	TSL:1 MANE Select	c.563G>A	p.Arg188His	missense	Exon 3 of 3	ENSP00000352271.1	O43543
	XRCC2	ENST00000495707.1	TSL:1	n.585G>A		non_coding_transcript_exon	Exon 3 of 3
	XRCC2	ENST00000698506.1		c.395G>A	p.Arg132His	missense	Exon 2 of 2	ENSP00000513758.1	A0A8V8TMB7

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8352 AN: 152070 Hom.: 338 Cov.: 32

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0577

Gnomad ASJ AF: 0.0910

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0803

Gnomad OTH AF: 0.0657

GnomAD2 exomes AF: 0.0636 AC: 15999 AN: 251360 AF XY: 0.0685

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.0410

Gnomad ASJ exome AF: 0.0834

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.0339

Gnomad NFE exome AF: 0.0803

Gnomad OTH exome AF: 0.0704

GnomAD4 exome AF: 0.0768 AC: 112337 AN: 1461872 Hom.: 4809 Cov.: 32 AF XY: 0.0783 AC XY: 56917 AN XY: 727230

African (AFR) AF: 0.0131 AC: 437 AN: 33478

American (AMR) AF: 0.0425 AC: 1902 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0853 AC: 2230 AN: 26136

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39698

South Asian (SAS) AF: 0.106 AC: 9139 AN: 86256

European-Finnish (FIN) AF: 0.0355 AC: 1894 AN: 53416

Middle Eastern (MID) AF: 0.0884 AC: 510 AN: 5768

European-Non Finnish (NFE) AF: 0.0824 AC: 91655 AN: 1112002

Other (OTH) AF: 0.0755 AC: 4558 AN: 60396

GnomAD4 genome AF: 0.0549 AC: 8349 AN: 152188 Hom.: 336 Cov.: 32 AF XY: 0.0541 AC XY: 4024 AN XY: 74390

African (AFR) AF: 0.0155 AC: 644 AN: 41536

American (AMR) AF: 0.0576 AC: 879 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0910 AC: 316 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.110 AC: 530 AN: 4824

European-Finnish (FIN) AF: 0.0301 AC: 319 AN: 10586

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0802 AC: 5454 AN: 67998

Other (OTH) AF: 0.0650 AC: 137 AN: 2108

Alfa AF: 0.0702 Hom.: 1239

Bravo AF: 0.0531

TwinsUK AF: 0.0855 AC: 317

ALSPAC AF: 0.0817 AC: 315

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.0773 AC: 665

ExAC AF: 0.0655 AC: 7955

Asia WGS AF: 0.0490 AC: 170 AN: 3478

EpiCase AF: 0.0781

EpiControl AF: 0.0812

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Fanconi anemia complementation group U (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.80
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.6
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.030
Sift	Benign	0.37	T
Sift4G	Benign	0.47	T
Polyphen		0.047	B
Vest4		0.029
MPC		0.043
ClinPred		0.0011	T
GERP RS		1.9
Varity_R		0.027
gMVP		0.27
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3218536; hg19: chr7-152346007; COSMIC: COSV63770283;