chr19-43551574-T-C

Variant names:

• chr19-43551574-T-C
• rs25487
• NM_006297.3:c.1196A>G

Variant summary

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

The NM_006297.3(XRCC1):​c.1196A>G​(p.Gln399Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.658 in 1,613,104 control chromosomes in the GnomAD database, including 351,454 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39067 hom., cov: 33)
  • Exomes 𝑓: 0.65 (312387 hom.)
• Consequence: XRCC1 NM_006297.3 missense
• Clinical Significance: drug response reviewed by expert panel B:2 O:1
• Conservation: PhyloP100: 1.98
• Publications: 1491 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 (MetaRNN=6.525281E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.845 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC1	NM_006297.3	MANE Select	c.1196A>G	p.Gln399Arg	missense	Exon 10 of 17	NP_006288.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC1	ENST00000262887.10	TSL:1 MANE Select	c.1196A>G	p.Gln399Arg	missense	Exon 10 of 17	ENSP00000262887.5
	XRCC1	ENST00000953258.1		c.1190A>G	p.Gln397Arg	missense	Exon 10 of 17	ENSP00000623317.1
	XRCC1	ENST00000865401.1		c.1193A>G	p.Gln398Arg	missense	Exon 10 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes AF: 0.711 AC: 108110 AN: 152018 Hom.: 39012 Cov.: 33

Gnomad AFR AF: 0.852

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.689

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.738

Gnomad SAS AF: 0.652

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.642

Gnomad OTH AF: 0.712

GnomAD2 exomes AF: 0.681 AC: 170473 AN: 250468 AF XY: 0.673

Gnomad AFR exome AF: 0.855

Gnomad AMR exome AF: 0.735

Gnomad ASJ exome AF: 0.618

Gnomad EAS exome AF: 0.742

Gnomad FIN exome AF: 0.688

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.662

GnomAD4 exome AF: 0.652 AC: 952451 AN: 1460968 Hom.: 312387 Cov.: 39 AF XY: 0.652 AC XY: 473566 AN XY: 726870

African (AFR) AF: 0.857 AC: 28686 AN: 33468

American (AMR) AF: 0.730 AC: 32640 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 16027 AN: 26128

East Asian (EAS) AF: 0.741 AC: 29396 AN: 39692

South Asian (SAS) AF: 0.647 AC: 55826 AN: 86232

European-Finnish (FIN) AF: 0.691 AC: 36866 AN: 53328

Middle Eastern (MID) AF: 0.711 AC: 4097 AN: 5764

European-Non Finnish (NFE) AF: 0.638 AC: 708635 AN: 1111278

Other (OTH) AF: 0.667 AC: 40278 AN: 60362

GnomAD4 genome AF: 0.711 AC: 108216 AN: 152136 Hom.: 39067 Cov.: 33 AF XY: 0.713 AC XY: 53053 AN XY: 74358

African (AFR) AF: 0.852 AC: 35385 AN: 41516

American (AMR) AF: 0.689 AC: 10536 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 2068 AN: 3470

East Asian (EAS) AF: 0.738 AC: 3815 AN: 5166

South Asian (SAS) AF: 0.652 AC: 3142 AN: 4820

European-Finnish (FIN) AF: 0.695 AC: 7359 AN: 10582

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.642 AC: 43663 AN: 67986

Other (OTH) AF: 0.710 AC: 1496 AN: 2108

Alfa AF: 0.664 Hom.: 71046

Bravo AF: 0.719

TwinsUK AF: 0.626 AC: 2320

ALSPAC AF: 0.646 AC: 2489

ESP6500AA AF: 0.845 AC: 3723

ESP6500EA AF: 0.640 AC: 5501

ExAC AF: 0.682 AC: 82838

Asia WGS AF: 0.709 AC: 2466 AN: 3478

EpiCase AF: 0.648

EpiControl AF: 0.650

ClinVar

ClinVar submissions as Germline

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Spinocerebellar ataxia, autosomal recessive 26 (1)
-	-	-	Platinum compounds response - Efficacy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	15
DANN	Benign	0.13
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.029	T
MetaRNN	Benign	6.5e-7	T
MetaSVM	Benign	-0.98	T
PhyloP100		2.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.072
Sift	Benign	1.0	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.057
MPC		0.23
ClinPred		0.0059	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.15
Mutation Taster		=93/7	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: rs25487; hg19: chr19-44055726; COSMIC: COSV53447249; COSMIC: COSV53447249;