rs3218438

Variant names:

• chr7-152666141-T-C
• rs3218438
• NM_005431.2:c.40-5359A>G

Variant summary

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

The NM_005431.2(XRCC2):​c.40-5359A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0687 in 152,294 control chromosomes in the GnomAD database, including 437 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 0.069 (437 hom., cov: 33)
• Consequence: XRCC2 NM_005431.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.488
• Publications: 2 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC2	NM_005431.2	c.40-5359A>G		intron_variant	Intron 1 of 2	ENST00000359321.2	NP_005422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC2	ENST00000359321.2	c.40-5359A>G		intron_variant	Intron 1 of 2	1	NM_005431.2	ENSP00000352271.1
XRCC2	ENST00000698506.1	c.-48+9900A>G		intron_variant	Intron 1 of 1			ENSP00000513758.1
XRCC2	ENST00000698507.1	n.108-5359A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0687 AC: 10458 AN: 152176 Hom.: 437 Cov.: 33

Gnomad AFR AF: 0.0358

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0616

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0443

Gnomad FIN AF: 0.0685

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0955

Gnomad OTH AF: 0.0669

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0687 AC: 10460 AN: 152294 Hom.: 437 Cov.: 33 AF XY: 0.0665 AC XY: 4953 AN XY: 74468

African (AFR) AF: 0.0358 AC: 1487 AN: 41584

American (AMR) AF: 0.0615 AC: 939 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 390 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.0448 AC: 216 AN: 4826

European-Finnish (FIN) AF: 0.0685 AC: 727 AN: 10610

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0955 AC: 6498 AN: 68022

Other (OTH) AF: 0.0662 AC: 140 AN: 2116

Alfa AF: 0.0801 Hom.: 69

Bravo AF: 0.0660

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.0
DANN	Benign	0.81
PhyloP100		0.49
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: rs3218438; hg19: chr7-152363226;