Genetic Variant XRCC1:p.Arg559Gln (chr19-43544180-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_006297.3(XRCC1):c.1676G>A(p.Arg559Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000969 in 1,610,792 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0010 ( 3 hom. )

Consequence

XRCC1
NM_006297.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.11

Publications

9 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0782063).

BP6

Variant 19-43544180-C-T is Benign according to our data. Variant chr19-43544180-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1879445.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 68 AD,Unknown gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC1	NM_006297.3	MANE Select	c.1676G>A	p.Arg559Gln	missense	Exon 15 of 17	NP_006288.2	P18887

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
XRCC1	ENST00000262887.10	TSL:1 MANE Select	c.1676G>A	p.Arg559Gln	missense	Exon 15 of 17	ENSP00000262887.5	P18887
XRCC1	ENST00000953258.1		c.1688G>A	p.Arg563Gln	missense	Exon 15 of 17	ENSP00000623317.1
XRCC1	ENST00000865401.1		c.1673G>A	p.Arg558Gln	missense	Exon 15 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000582

AC:

143

AN:

245708

AF XY:

0.000513

show subpopulations

Gnomad AFR exome

AF:

0.000322

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000332

Gnomad NFE exome

AF:

0.00117

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.00102

AC:

1493

AN:

1458702

Hom.:

Cov.:

AF XY:

0.000960

AC XY:

696

AN XY:

725138

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33436

American (AMR)

AF:

0.00

AC:

AN:

44234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26006

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39668

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85358

European-Finnish (FIN)

AF:

0.000338

AC:

AN:

53236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00121

AC:

1343

AN:

1110660

Other (OTH)

AF:

0.00199

AC:

120

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

149

224

298

373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.000447

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41410

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000838

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000801

Hom.:

Bravo

AF:

0.000533

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000684

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.082

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.078

MetaSVM

Uncertain

-0.081

PhyloP100

2.1

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.55

Sift

Benign

0.048

Sift4G

Uncertain

0.025

Polyphen

0.0020

Vest4

0.50

MVP

0.65

MPC

0.48

ClinPred

0.062

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.62

Mutation Taster

=92/8

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over