rs2307177

Positions:

• chr19-43543673-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006297.3(XRCC1):​c.1727A>C​(p.Tyr576Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0123 in 1,613,906 control chromosomes in the GnomAD database, including 198 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y576N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (42 hom., cov: 30)
  • Exomes 𝑓: 0.012 (156 hom.)
• Consequence: XRCC1 NM_006297.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.06

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007240653).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0195 (2959/152036) while in subpopulation AFR AF= 0.0378 (1567/41428). AF 95% confidence interval is 0.0363. There are 42 homozygotes in gnomad4. There are 1402 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC1	NM_006297.3	c.1727A>C	p.Tyr576Ser	missense_variant	16/17	ENST00000262887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC1	ENST00000262887.10	c.1727A>C	p.Tyr576Ser	missense_variant	16/17	1	NM_006297.3	P1
XRCC1	ENST00000543982.5	c.1634A>C	p.Tyr545Ser	missense_variant	15/16	2

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2954 AN: 151918 Hom.: 42 Cov.: 30

Gnomad AFR AF: 0.0378

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0211

GnomAD3 exomes AF: 0.0123 AC: 3100 AN: 251426 Hom.: 34 AF XY: 0.0126 AC XY: 1708 AN XY: 135878

Gnomad AFR exome AF: 0.0384

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0138

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.0192

GnomAD4 exome AF: 0.0116 AC: 16921 AN: 1461870 Hom.: 156 Cov.: 34 AF XY: 0.0116 AC XY: 8440 AN XY: 727240

Gnomad4 AFR exome AF: 0.0424

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.0192

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0148

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.0195 AC: 2959 AN: 152036 Hom.: 42 Cov.: 30 AF XY: 0.0189 AC XY: 1402 AN XY: 74312

Gnomad4 AFR AF: 0.0378

Gnomad4 AMR AF: 0.0233

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0148

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.0209

Alfa AF: 0.0132 Hom.: 24

Bravo AF: 0.0225

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.0186 AC: 82

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.0125 AC: 1514

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0146

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.0027
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D
MetaRNN	Benign	0.0072	T;T
MutationTaster	Benign	1.0	N;N
Sift4G	Benign	0.11	T;T
Vest4		0.53
ClinPred		0.022	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs2307177; hg19: chr19-44047825; COSMIC: COSV53450474;