Genetic Variant XRCC1:p.Pro206Pro (chr19-43553075-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006297.3(XRCC1):c.618A>G(p.Pro206Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 1,576,866 control chromosomes in the GnomAD database, including 142,540 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12555 hom., cov: 32)

Exomes 𝑓: 0.42 ( 129985 hom. )

Consequence

XRCC1
NM_006297.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.46

Publications

58 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 19-43553075-T-C is Benign according to our data. Variant chr19-43553075-T-C is described in ClinVar as Benign. ClinVar VariationId is 1684240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.46 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC1	NM_006297.3 link	c.618A>G	p.Pro206Pro	synonymous_variant	Exon 7 of 17	ENST00000262887.10	NP_006288.2	P18887B2RCY5Q59HH7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC1	ENST00000262887.10 link	c.618A>G	p.Pro206Pro	synonymous_variant	Exon 7 of 17	1	NM_006297.3	ENSP00000262887.5		P18887

Frequencies

GnomAD3 genomes

AF:

0.400

AC:

60741

AN:

151870

Hom.:

12547

Cov.:

show subpopulations

Gnomad AFR

AF:

0.395

Gnomad AMI

AF:

0.418

Gnomad AMR

AF:

0.302

Gnomad ASJ

AF:

0.335

Gnomad EAS

AF:

0.114

Gnomad SAS

AF:

0.370

Gnomad FIN

AF:

0.460

Gnomad MID

AF:

0.339

Gnomad NFE

AF:

0.443

Gnomad OTH

AF:

0.390

GnomAD2 exomes

AF:

0.366

AC:

70755

AN:

193098

AF XY:

0.375

show subpopulations

Gnomad AFR exome

AF:

0.394

Gnomad AMR exome

AF:

0.212

Gnomad ASJ exome

AF:

0.345

Gnomad EAS exome

AF:

0.109

Gnomad FIN exome

AF:

0.451

Gnomad NFE exome

AF:

0.437

Gnomad OTH exome

AF:

0.385

GnomAD4 exome

AF:

0.420

AC:

598441

AN:

1424878

Hom.:

129985

Cov.:

AF XY:

0.421

AC XY:

296605

AN XY:

705218

show subpopulations

African (AFR)

AF:

0.397

AC:

13025

AN:

32846

American (AMR)

AF:

0.220

AC:

8521

AN:

38702

Ashkenazi Jewish (ASJ)

AF:

0.340

AC:

8649

AN:

25424

East Asian (EAS)

AF:

0.103

AC:

3966

AN:

38434

South Asian (SAS)

AF:

0.387

AC:

31614

AN:

81604

European-Finnish (FIN)

AF:

0.455

AC:

23278

AN:

51124

Middle Eastern (MID)

AF:

0.353

AC:

1646

AN:

4664

European-Non Finnish (NFE)

AF:

0.443

AC:

484153

AN:

1093098

Other (OTH)

AF:

0.400

AC:

23589

AN:

58982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

18807

37614

56422

75229

94036

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14560

29120

43680

58240

72800

<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:

0.400

AC:

60793

AN:

151988

Hom.:

12555

Cov.:

AF XY:

0.397

AC XY:

29497

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.395

AC:

16378

AN:

41438

American (AMR)

AF:

0.301

AC:

4604

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.335

AC:

1163

AN:

3470

East Asian (EAS)

AF:

0.115

AC:

593

AN:

5176

South Asian (SAS)

AF:

0.371

AC:

1789

AN:

4820

European-Finnish (FIN)

AF:

0.460

AC:

4850

AN:

10550

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.443

AC:

30112

AN:

67940

Other (OTH)

AF:

0.389

AC:

821

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1870

3739

5609

7478

9348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

582

1164

1746

2328

2910

<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:

0.413

Hom.:

8616

Bravo

AF:

0.382

Asia WGS

AF:

0.258

AC:

904

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.068

(source)

DANN

Benign

0.49

PhyloP100

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over