rs25487

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

drug response reviewed by expert panel B:2O:1

Conservation

PhyloP100: 1.98

Publications

1491 publications found

Variant links:

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)

XRCC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC1	NM_006297.3 link	c.1196A>G	p.Gln399Arg	missense_variant	Exon 10 of 17	ENST00000262887.10	NP_006288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
XRCC1	ENST00000262887.10 link	c.1196A>G	p.Gln399Arg	missense_variant	Exon 10 of 17	1	NM_006297.3	ENSP00000262887.5
XRCC1	ENST00000543982.5 link	c.1103A>G	p.Gln368Arg	missense_variant	Exon 9 of 16	2		ENSP00000443671.1
XRCC1	ENST00000597811.5 link	n.*310A>G		non_coding_transcript_exon_variant	Exon 7 of 7	5		ENSP00000470391.1
XRCC1	ENST00000597811.5 link	n.*310A>G		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000470391.1

Frequencies

GnomAD3 genomes

AF:

0.711

AC:

108110

AN:

152018

Hom.:

39012

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.652

AC XY:

473566

AN XY:

726870

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

17683

35367

53050

70734

88417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18874

37748

56622

75496

94370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.711

AC:

108216

AN:

152136

Hom.:

39067

Cov.:

AF XY:

0.713

AC XY:

53053

AN XY:

74358

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1594

3188

4783

6377

7971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

830

1660

2490

3320

4150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Significance: drug response

Submissions summary: Benign:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Spinocerebellar ataxia, autosomal recessive 26

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jul 31, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21427728, 15113441, 19481337, 11782372, 23479765, 14630517, 21843798, 22053659, 22951806, 24176953, 22224629, 22106831, 23360319, 21987112, 21928248, 18641418, 22193858, 19012493, 22525558, 22712837, 19880550, 22302399, 22983827, 21617750, 20431719, 23499241, 19465687, 20385586, 18357393, 21647176, 19051060, 23055018, 17961713, 22868082, 22568010, 19428062, 11104903, 24205020) -

Platinum compounds response - Efficacy

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.13

DEOGEN2

Benign

0.0072

.;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.029

.;T

MetaRNN

Benign

6.5e-7

T;T

MetaSVM

Benign

-0.98

PhyloP100

2.0

PrimateAI

Uncertain

0.72

PROVEAN

Benign

2.1

N;N

REVEL

Benign

0.072

Sift

Benign

1.0

T;T

Sift4G

Benign

0.88

T;T

Polyphen

0.0

.;B

Vest4

0.057

MPC

0.23

ClinPred

0.0059

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)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over