7-152648413-GAAAAAAA-GAAA

Variant names:

• chr7-152648413-GAAAA-G
• rs10707642
• NM_005431.2:c.*225_*228delTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005431.2(XRCC2):​c.*225_*228delTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000269 in 260,578 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: XRCC2 NM_005431.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.347
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.*225_*228delTTTT		3_prime_UTR	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.*225_*228delTTTT		3_prime_UTR	Exon 3 of 3	ENSP00000352271.1	O43543
	XRCC2	ENST00000495707.1	TSL:1	n.1090_1093delTTTT		non_coding_transcript_exon	Exon 3 of 3
	XRCC2	ENST00000698506.1		c.*225_*228delTTTT		3_prime_UTR	Exon 2 of 2	ENSP00000513758.1	A0A8V8TMB7

Frequencies

GnomAD3 genomes AF: 0.0000283 AC: 4 AN: 141494 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000458

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000554 AC: 66 AN: 119084 Hom.: 0 AF XY: 0.000557 AC XY: 33 AN XY: 59194

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

African (AFR) AF: 0.000501 AC: 2 AN: 3990

American (AMR) AF: 0.000437 AC: 2 AN: 4572

Ashkenazi Jewish (ASJ) AF: 0.000202 AC: 1 AN: 4946

East Asian (EAS) AF: 0.0000950 AC: 1 AN: 10524

South Asian (SAS) AF: 0.000560 AC: 2 AN: 3574

European-Finnish (FIN) AF: 0.000858 AC: 4 AN: 4664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 626

European-Non Finnish (NFE) AF: 0.000667 AC: 52 AN: 77980

Other (OTH) AF: 0.000244 AC: 2 AN: 8208

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000283 AC: 4 AN: 141494 Hom.: 0 Cov.: 0 AF XY: 0.0000293 AC XY: 2 AN XY: 68354

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

African (AFR) AF: 0.00 AC: 0 AN: 37690

American (AMR) AF: 0.00 AC: 0 AN: 14190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3340

East Asian (EAS) AF: 0.00 AC: 0 AN: 4794

South Asian (SAS) AF: 0.00 AC: 0 AN: 4490

European-Finnish (FIN) AF: 0.000119 AC: 1 AN: 8398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000458 AC: 3 AN: 65482

Other (OTH) AF: 0.00 AC: 0 AN: 1932

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0188335), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 839

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism

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: rs10707642; hg19: chr7-152345498;