rs1799782

Positions:

• chr19-43553422-G-A
• chr19-43553422-G-C
• chr19-43553422-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000262887.10(XRCC1):​c.580C>T​(p.Arg194Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0714 in 1,613,942 control chromosomes in the GnomAD database, including 5,979 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (622 hom., cov: 31)
  • Exomes 𝑓: 0.071 (5357 hom.)
• Consequence: XRCC1 ENST00000262887.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.53

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016328394).
• BP6: Variant 19-43553422-G-A is Benign according to our data. Variant chr19-43553422-G-A is described in ClinVar as [Benign]. Clinvar id is 376355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRCC1	NM_006297.3	c.580C>T	p.Arg194Trp	missense_variant	6/17	ENST00000262887.10	NP_006288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRCC1	ENST00000262887.10	c.580C>T	p.Arg194Trp	missense_variant	6/17	1	NM_006297.3	ENSP00000262887	P1
	ENST00000597119.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0733 AC: 11141 AN: 152008 Hom.: 622 Cov.: 31

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0591

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0370

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0616

Gnomad OTH AF: 0.0852

GnomAD3 exomes AF: 0.0946 AC: 23794 AN: 251438 Hom.: 1703 AF XY: 0.0905 AC XY: 12298 AN XY: 135900

Gnomad AFR exome AF: 0.0599

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.0686

Gnomad EAS exome AF: 0.305

Gnomad SAS exome AF: 0.0935

Gnomad FIN exome AF: 0.0361

Gnomad NFE exome AF: 0.0621

Gnomad OTH exome AF: 0.0831

GnomAD4 exome AF: 0.0712 AC: 104065 AN: 1461816 Hom.: 5357 Cov.: 33 AF XY: 0.0715 AC XY: 51968 AN XY: 727210

Gnomad4 AFR exome AF: 0.0639

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.0657

Gnomad4 EAS exome AF: 0.304

Gnomad4 SAS exome AF: 0.0923

Gnomad4 FIN exome AF: 0.0370

Gnomad4 NFE exome AF: 0.0597

Gnomad4 OTH exome AF: 0.0803

GnomAD4 genome AF: 0.0732 AC: 11143 AN: 152126 Hom.: 622 Cov.: 31 AF XY: 0.0739 AC XY: 5495 AN XY: 74364

Gnomad4 AFR AF: 0.0622

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.0591

Gnomad4 EAS AF: 0.292

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.0370

Gnomad4 NFE AF: 0.0616

Gnomad4 OTH AF: 0.0852

Alfa AF: 0.0682 Hom.: 958

Bravo AF: 0.0800

TwinsUK AF: 0.0604 AC: 224

ALSPAC AF: 0.0579 AC: 223

ESP6500AA AF: 0.0561 AC: 247

ESP6500EA AF: 0.0645 AC: 555

ExAC AF: 0.0928 AC: 11262

Asia WGS AF: 0.189 AC: 657 AN: 3478

EpiCase AF: 0.0694

EpiControl AF: 0.0674

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2020	This variant is associated with the following publications: (PMID: 17630853, 26434847, 25227852, 25340946, 24497981, 25169084, 24039945, 23990873, 23320983, 22639094, 29484706, 19124519, 16324877, 20385586, 19465687, 20431719, 22983827, 21499756, 20553853, 21987112, 12893086, 20218899, 20331623, 20863780, 20332227, 20052722, 19481337, 15113441) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.086	.;T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.84	.;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.000030	P;P
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.4	D;D;.;.
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.
Polyphen		0.91	.;P;.;.
Vest4		0.32
MPC		0.56
ClinPred		0.041	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1799782; hg19: chr19-44057574; COSMIC: COSV53447553; COSMIC: COSV53447553;