chr19-43553422-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006297.3(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 (★★). Synonymous variant affecting the same amino acid position (i.e. R194R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.073 ( 622 hom., cov: 31)

Exomes 𝑓: 0.071 ( 5357 hom. )

Consequence

XRCC1
NM_006297.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.53

Publications

872 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:

ENSG00000269177 (HGNC:):

ENSG00000269177 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

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.580C>T	p.Arg194Trp	missense	Exon 6 of 17	NP_006288.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
XRCC1	ENST00000262887.10	TSL:1 MANE Select	c.580C>T	p.Arg194Trp	missense	Exon 6 of 17	ENSP00000262887.5
XRCC1	ENST00000953258.1		c.580C>T	p.Arg194Trp	missense	Exon 6 of 17	ENSP00000623317.1
XRCC1	ENST00000865401.1		c.577C>T	p.Arg193Trp	missense	Exon 6 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes

AF:

0.0733

AC:

11141

AN:

152008

Hom.:

622

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0946

AC:

23794

AN:

251438

AF XY:

0.0905

show subpopulations

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 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.:

AF XY:

0.0715

AC XY:

51968

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.0639

AC:

2140

AN:

33478

American (AMR)

AF:

0.146

AC:

6514

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0657

AC:

1718

AN:

26136

East Asian (EAS)

AF:

0.304

AC:

12072

AN:

39696

South Asian (SAS)

AF:

0.0923

AC:

7965

AN:

86256

European-Finnish (FIN)

AF:

0.0370

AC:

1975

AN:

53414

Middle Eastern (MID)

AF:

0.0788

AC:

454

AN:

5764

European-Non Finnish (NFE)

AF:

0.0597

AC:

66380

AN:

1111956

Other (OTH)

AF:

0.0803

AC:

4847

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

5448

10897

16345

21794

27242

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2682

5364

8046

10728

13410

<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:

0.0732

AC:

11143

AN:

152126

Hom.:

622

Cov.:

AF XY:

0.0739

AC XY:

5495

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0622

AC:

2580

AN:

41500

American (AMR)

AF:

0.101

AC:

1549

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0591

AC:

205

AN:

3468

East Asian (EAS)

AF:

0.292

AC:

1507

AN:

5154

South Asian (SAS)

AF:

0.103

AC:

495

AN:

4810

European-Finnish (FIN)

AF:

0.0370

AC:

393

AN:

10608

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0616

AC:

4186

AN:

67980

Other (OTH)

AF:

0.0852

AC:

180

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

508

1015

1523

2030

2538

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<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:

0.0703

Hom.:

2201

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.086

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.96

PhyloP100

1.5

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.4

REVEL

Benign

0.20

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.91

Vest4

0.32

MPC

0.56

ClinPred

0.041

GERP RS

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.68

Mutation Taster

=81/19

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over