rs2682558

Variant names:

• chr19-43543164-C-T
• rs2682558
• NM_006297.3:c.*228G>A

Variant summary

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

The NM_006297.3(XRCC1):​c.*228G>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 459,756 control chromosomes in the GnomAD database, including 7,584 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 0.19 (2078 hom., cov: 27)
  • Exomes 𝑓: 0.18 (5506 hom.)
• Consequence: XRCC1 NM_006297.3 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168
• Publications: 6 publications found

Genes affected

XRCC1 (HGNC:12828): (X-ray repair cross complementing 1) The protein encoded by this gene is involved in the efficient repair of DNA single-strand breaks formed by exposure to ionizing radiation and alkylating agents. This protein interacts with DNA ligase III, polymerase beta and poly (ADP-ribose) polymerase to participate in the base excision repair pathway. It may play a role in DNA processing during meiogenesis and recombination in germ cells. A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity. [provided by RefSeq, Jul 2008]

XRCC1 Gene-Disease associations (from GenCC):

• head and neck cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• spinocerebellar ataxia, autosomal recessive 26

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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 (NFE) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006297.3. 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
	XRCC1	NM_006297.3	MANE Select	c.*228G>A		downstream_gene	N/A	NP_006288.2	P18887

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC1	ENST00000262887.10	TSL:1 MANE Select	c.*228G>A		downstream_gene	N/A	ENSP00000262887.5	P18887
	XRCC1	ENST00000953258.1		c.*228G>A		downstream_gene	N/A	ENSP00000623317.1
	XRCC1	ENST00000865401.1		c.*228G>A		downstream_gene	N/A	ENSP00000535460.1

Frequencies

GnomAD3 genomes AF: 0.190 AC: 24559 AN: 129596 Hom.: 2080 Cov.: 27

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.00230

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.167

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.179

GnomAD4 exome AF: 0.183 AC: 60443 AN: 330048 Hom.: 5506 Cov.: 2 AF XY: 0.183 AC XY: 32060 AN XY: 175270

African (AFR) AF: 0.181 AC: 1604 AN: 8840

American (AMR) AF: 0.151 AC: 1679 AN: 11086

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 1546 AN: 10338

East Asian (EAS) AF: 0.000442 AC: 8 AN: 18084

South Asian (SAS) AF: 0.160 AC: 6048 AN: 37810

European-Finnish (FIN) AF: 0.199 AC: 4172 AN: 20924

Middle Eastern (MID) AF: 0.175 AC: 243 AN: 1386

European-Non Finnish (NFE) AF: 0.206 AC: 41709 AN: 202882

Other (OTH) AF: 0.184 AC: 3434 AN: 18698

GnomAD4 genome AF: 0.189 AC: 24571 AN: 129708 Hom.: 2078 Cov.: 27 AF XY: 0.187 AC XY: 11798 AN XY: 63040

African (AFR) AF: 0.184 AC: 6233 AN: 33896

American (AMR) AF: 0.167 AC: 1938 AN: 11620

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 435 AN: 3110

East Asian (EAS) AF: 0.00230 AC: 9 AN: 3908

South Asian (SAS) AF: 0.138 AC: 607 AN: 4394

European-Finnish (FIN) AF: 0.207 AC: 1808 AN: 8732

Middle Eastern (MID) AF: 0.164 AC: 41 AN: 250

European-Non Finnish (NFE) AF: 0.212 AC: 12971 AN: 61108

Other (OTH) AF: 0.176 AC: 316 AN: 1792

Alfa AF: 0.163 Hom.: 356

Bravo AF: 0.158

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	8.2
DANN	Benign	0.75
PhyloP100		-0.17
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: rs2682558; hg19: chr19-44047316;