rs2139720

Variant names:

• chr19-43551430-C-T
• rs2139720
• NM_006297.3:c.1199+141G>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.1199+141G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 713,160 control chromosomes in the GnomAD database, including 17,909 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 0.21 (3496 hom., cov: 32)
  • Exomes 𝑓: 0.22 (14413 hom.)
• Consequence: XRCC1 NM_006297.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.369
• Publications: 8 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC1	NM_006297.3	c.1199+141G>A		intron_variant	Intron 10 of 16	ENST00000262887.10	NP_006288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC1	ENST00000262887.10	c.1199+141G>A		intron_variant	Intron 10 of 16	1	NM_006297.3	ENSP00000262887.5
XRCC1	ENST00000543982.5	c.1106+141G>A		intron_variant	Intron 9 of 15	2		ENSP00000443671.1
XRCC1	ENST00000597811.5	n.*454G>A		downstream_gene_variant		5		ENSP00000470391.1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31917 AN: 152050 Hom.: 3496 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.205

GnomAD4 exome AF: 0.219 AC: 122656 AN: 560992 Hom.: 14413 AF XY: 0.221 AC XY: 64850 AN XY: 293958

African (AFR) AF: 0.184 AC: 2837 AN: 15452

American (AMR) AF: 0.114 AC: 3060 AN: 26812

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 2882 AN: 15404

East Asian (EAS) AF: 0.102 AC: 3265 AN: 31862

South Asian (SAS) AF: 0.225 AC: 11951 AN: 53216

European-Finnish (FIN) AF: 0.280 AC: 8938 AN: 31956

Middle Eastern (MID) AF: 0.145 AC: 475 AN: 3282

European-Non Finnish (NFE) AF: 0.235 AC: 82822 AN: 353074

Other (OTH) AF: 0.215 AC: 6426 AN: 29934

GnomAD4 genome AF: 0.210 AC: 31953 AN: 152168 Hom.: 3496 Cov.: 32 AF XY: 0.210 AC XY: 15603 AN XY: 74360

African (AFR) AF: 0.182 AC: 7578 AN: 41528

American (AMR) AF: 0.141 AC: 2156 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 675 AN: 3466

East Asian (EAS) AF: 0.111 AC: 576 AN: 5176

South Asian (SAS) AF: 0.228 AC: 1102 AN: 4826

European-Finnish (FIN) AF: 0.281 AC: 2967 AN: 10572

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16270 AN: 68002

Other (OTH) AF: 0.206 AC: 435 AN: 2112

Alfa AF: 0.222 Hom.: 469

Bravo AF: 0.194

Asia WGS AF: 0.189 AC: 658 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.87
PhyloP100		-0.37
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: rs2139720; hg19: chr19-44055582; COSMIC: COSV53451539; COSMIC: COSV53451539;