Genetic Variant XRCC1:c.*228G>A (chr19-43543164-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_006297.3(XRCC1):c.*228G>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 459,756 control chromosomes in the GnomAD database, including 7,584 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.

Frequency

Genomes: 𝑓 0.19 ( 2078 hom., cov: 27)

Exomes 𝑓: 0.18 ( 5506 hom. )

Consequence

XRCC1
NM_006297.3 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.168

Publications

6 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 (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC1	NM_006297.3 link	c.*228G>A		downstream_gene_variant		ENST00000262887.10	NP_006288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC1	ENST00000262887.10 link	c.*228G>A		downstream_gene_variant		1	NM_006297.3	ENSP00000262887.5
XRCC1	ENST00000543982.5 link	c.*228G>A		downstream_gene_variant		2		ENSP00000443671.1

Frequencies

GnomAD3 genomes

AF:

0.190

AC:

24559

AN:

129596

Hom.:

2080

Cov.:

show subpopulations

Gnomad AFR

AF:

0.184

Gnomad AMI

AF:

0.237

Gnomad AMR

AF:

0.167

Gnomad ASJ

AF:

0.140

Gnomad EAS

AF:

0.00230

Gnomad SAS

AF:

0.137

Gnomad FIN

AF:

0.207

Gnomad MID

AF:

0.167

Gnomad NFE

AF:

0.212

Gnomad OTH

AF:

0.179

GnomAD4 exome

AF:

0.183

AC:

60443

AN:

330048

Hom.:

5506

Cov.:

AF XY:

0.183

AC XY:

32060

AN XY:

175270

show subpopulations

African (AFR)

AF:

0.181

AC:

1604

AN:

8840

American (AMR)

AF:

0.151

AC:

1679

AN:

11086

Ashkenazi Jewish (ASJ)

AF:

0.150

AC:

1546

AN:

10338

East Asian (EAS)

AF:

0.000442

AC:

AN:

18084

South Asian (SAS)

AF:

0.160

AC:

6048

AN:

37810

European-Finnish (FIN)

AF:

0.199

AC:

4172

AN:

20924

Middle Eastern (MID)

AF:

0.175

AC:

243

AN:

1386

European-Non Finnish (NFE)

AF:

0.206

AC:

41709

AN:

202882

Other (OTH)

AF:

0.184

AC:

3434

AN:

18698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

2236

4472

6708

8944

11180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

204

408

612

816

1020

<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:

0.189

AC:

24571

AN:

129708

Hom.:

2078

Cov.:

AF XY:

0.187

AC XY:

11798

AN XY:

63040

show subpopulations

African (AFR)

AF:

0.184

AC:

6233

AN:

33896

American (AMR)

AF:

0.167

AC:

1938

AN:

11620

Ashkenazi Jewish (ASJ)

AF:

0.140

AC:

435

AN:

3110

East Asian (EAS)

AF:

0.00230

AC:

AN:

3908

South Asian (SAS)

AF:

0.138

AC:

607

AN:

4394

European-Finnish (FIN)

AF:

0.207

AC:

1808

AN:

8732

Middle Eastern (MID)

AF:

0.164

AC:

AN:

250

European-Non Finnish (NFE)

AF:

0.212

AC:

12971

AN:

61108

Other (OTH)

AF:

0.176

AC:

316

AN:

1792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

974

1948

2923

3897

4871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

278

556

834

1112

1390

<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:

0.163

Hom.:

356

Bravo

AF:

0.158

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

8.2

(source)

DANN

Benign

0.75

PhyloP100

-0.17

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over