rs3218556

Variant names:

• chr7-152646516-G-A
• rs3218556
• ENST00000495707.1:n.2991C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000495707.1(XRCC2):​n.2991C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 152,140 control chromosomes in the GnomAD database, including 1,168 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (1168 hom., cov: 33)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: XRCC2 ENST00000495707.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.137
• Publications: 5 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000298894 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC2	NM_005431.2	c.*2126C>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000359321.2	NP_005422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC2	ENST00000495707.1	n.2991C>T		non_coding_transcript_exon_variant	Exon 3 of 3	1
XRCC2	ENST00000359321.2	c.*2126C>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_005431.2	ENSP00000352271.1
ENSG00000298894	ENST00000758786.1	n.253+11468G>A		intron_variant	Intron 2 of 2
XRCC2	ENST00000698506.1	c.*2126C>T		downstream_gene_variant				ENSP00000513758.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15429 AN: 151954 Hom.: 1159 Cov.: 33

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0461

Gnomad OTH AF: 0.113

GnomAD4 exome AF: 0.0143 AC: 1 AN: 70 Hom.: 0 Cov.: 0 AF XY: 0.0208 AC XY: 1 AN XY: 48

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60

Other (OTH) AF: 0.00 AC: 0 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.102 AC: 15464 AN: 152070 Hom.: 1168 Cov.: 33 AF XY: 0.103 AC XY: 7654 AN XY: 74340

African (AFR) AF: 0.162 AC: 6729 AN: 41472

American (AMR) AF: 0.212 AC: 3231 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 375 AN: 3472

East Asian (EAS) AF: 0.173 AC: 892 AN: 5168

South Asian (SAS) AF: 0.109 AC: 524 AN: 4806

European-Finnish (FIN) AF: 0.0200 AC: 212 AN: 10580

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0461 AC: 3136 AN: 68002

Other (OTH) AF: 0.114 AC: 241 AN: 2112

Alfa AF: 0.0787 Hom.: 95

Bravo AF: 0.121

Asia WGS AF: 0.166 AC: 577 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.1
DANN	Benign	0.73
PhyloP100		0.14
Mutation Taster		=100/0	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: rs3218556; hg19: chr7-152343601; COSMIC: COSV63770431;