NM_005431.2:c.40-2549T>C

Variant names:

• chr7-152663331-A-G
• rs3218455
• NM_005431.2:c.40-2549T>C

Variant summary

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

The NM_005431.2(XRCC2):​c.40-2549T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.06 in 124,536 control chromosomes in the GnomAD database, including 302 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 0.060 (302 hom., cov: 24)
• Consequence: XRCC2 NM_005431.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37
• Publications: 4 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

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 (SAS) allele frequency at 95% confidence interval = 0.104 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.40-2549T>C		intron	N/A	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.40-2549T>C		intron	N/A	ENSP00000352271.1	O43543
	XRCC2	ENST00000495707.1	TSL:1	n.61+613T>C		intron	N/A
	XRCC2	ENST00000698506.1		c.-48+12710T>C		intron	N/A	ENSP00000513758.1	A0A8V8TMB7

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 7466 AN: 124428 Hom.: 302 Cov.: 24

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.0435

Gnomad AMR AF: 0.0630

Gnomad ASJ AF: 0.0927

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0358

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0842

Gnomad OTH AF: 0.0668

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

GnomAD4 genome AF: 0.0600 AC: 7468 AN: 124536 Hom.: 302 Cov.: 24 AF XY: 0.0606 AC XY: 3532 AN XY: 58240

African (AFR) AF: 0.0179 AC: 614 AN: 34230

American (AMR) AF: 0.0629 AC: 672 AN: 10676

Ashkenazi Jewish (ASJ) AF: 0.0927 AC: 295 AN: 3184

East Asian (EAS) AF: 0.00 AC: 0 AN: 3816

South Asian (SAS) AF: 0.113 AC: 414 AN: 3664

European-Finnish (FIN) AF: 0.0358 AC: 202 AN: 5644

Middle Eastern (MID) AF: 0.113 AC: 24 AN: 212

European-Non Finnish (NFE) AF: 0.0841 AC: 5100 AN: 60620

Other (OTH) AF: 0.0662 AC: 113 AN: 1708

Alfa AF: 0.0622 Hom.: 58

Bravo AF: 0.0538

Asia WGS AF: 0.0500 AC: 173 AN: 3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.4
DANN	Benign	0.74
PhyloP100		1.4
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: rs3218455; hg19: chr7-152360416;