NM_005431.2:c.122-5469C>G

Variant names:

• chr7-152654832-G-C
• rs3218501
• NM_005431.2:c.122-5469C>G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_005431.2(XRCC2):c.122-5469C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0867 (AC=13,206) in the gnomAD database across 152,246 control chromosomes, including 945 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.196. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.087 (945 hom., cov: 33)
• Consequence: XRCC2 NM_005431.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.904
• Publications: 6 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, LiferaOmics
• 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:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1964 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	XRCC2 NM_005431.2	MANE Select	c.122-5469C>G	intron	Intron 2 of 2	Prot: NP_005422.1 UniProt:

XRCC2 NM_005431.2

MANE Select

HGVSc / HGVSpc.122-5469C>G

Exon rankIntron 2 of 2

intron

Prot: NP_005422.1UniProt: A0A384MEK2O43543

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	XRCC2 ENST00000359321.2	TSL:1MANE Select	c.122-5469C>G	intron	Intron 2 of 2	Prot: ENSP00000352271.1 UniProt:
	XRCC2 ENST00000495707.1	TSL:1	n.144-5469C>G	intron	Intron 2 of 2	Prot:
	XRCC2 ENST00000698506.1		c.-47-5469C>G	intron	Intron 1 of 1	Prot: ENSP00000513758.1 UniProt:

XRCC2 ENST00000359321.2

TSL:1MANE Select

HGVSc / HGVSpc.122-5469C>G

Exon rankIntron 2 of 2

intron

Prot: ENSP00000352271.1UniProt: O43543

XRCC2 ENST00000495707.1

TSL:1

HGVSc / HGVSpn.144-5469C>G

Exon rankIntron 2 of 2

intron

Prot:

XRCC2 ENST00000698506.1

HGVSc / HGVSpc.-47-5469C>G

Exon rankIntron 1 of 1

intron

Prot: ENSP00000513758.1UniProt: A0A8V8TMB7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0867	AC:13187	Hom:943	AN:152128	Cov:33
GnomAD4 genome	AF: 0.0867	AC:13206	Hom:945	AN:152246	Cov:33
TOPMed (Bravo)	AF: 0.0925	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0264	AC:599	Hom:42	AN:22684	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0867	AC:203	Hom:7	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.115	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0333	AC:10	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.0980	AC:339	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.120	AC:865	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.114	AC:20	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.142	AC:17414	Hom:1289	AN:122794	Cov:
Turkish Variome	AF: 0.0479	AC:74	Hom:5	AN:1546	Cov:
UK10K	AF: 0.0345	AC:261	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.127	AC:1137	Hom:75	AN:8960	Cov:

Showing 14 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	5.1
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.0
DANN	Benign	0.48
GPN-Star LLR	N/A	-3.8
GPN-Star score	N/A	3.8
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.90

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs3218501;

hg19: chr7-152351917;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar