19-43543412-C-T

Position:

• chr19-43543412-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006297.3(XRCC1):​c.1882G>A​(p.Gly628Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: XRCC1 NM_006297.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27162793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRCC1	NM_006297.3	c.1882G>A	p.Gly628Arg	missense_variant	17/17	ENST00000262887.10	NP_006288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRCC1	ENST00000262887.10	c.1882G>A	p.Gly628Arg	missense_variant	17/17	1	NM_006297.3	ENSP00000262887.5
XRCC1	ENST00000543982.5	c.1789G>A	p.Gly597Arg	missense_variant	16/16	2		ENSP00000443671.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2022

The c.1882G>A (p.G628R) alteration is located in exon 17 (coding exon 17) of the XRCC1 gene. This alteration results from a G to A substitution at nucleotide position 1882, causing the glycine (G) at amino acid position 628 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0065	.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.77	N;N
REVEL	Benign	0.11
Sift	Benign	0.48	T;D
Sift4G	Benign	0.64	T;T
Polyphen		1.0	.;D
Vest4		0.50
MutPred		0.35		Gain of solvent accessibility (P = 6e-04);.;
MVP		0.34
MPC		0.89
ClinPred		0.83	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-44047564;