NM_004628.5:c.2061G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004628.5(XPC):c.2061G>A(p.Arg687Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,611,184 control chromosomes in the GnomAD database, including 56,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5328 hom., cov: 32)

Exomes 𝑓: 0.26 ( 51627 hom. )

Consequence

XPC
NM_004628.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 2.36

Publications

29 publications found

Variant links:

Genes affected

XPC (HGNC:12816): (XPC complex subunit, DNA damage recognition and repair factor) The protein encoded by this gene is a key component of the XPC complex, which plays an important role in the early steps of global genome nucleotide excision repair (NER). The encoded protein is important for damage sensing and DNA binding, and shows a preference for single-stranded DNA. Mutations in this gene or some other NER components can result in Xeroderma pigmentosum, a rare autosomal recessive disorder characterized by increased sensitivity to sunlight with the development of carcinomas at an early age. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

XPC links:

XPC-AS1 (HGNC:55014): (XPC antisense RNA 1)

XPC-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.058).

BP6

Variant 3-14152389-C-T is Benign according to our data. Variant chr3-14152389-C-T is described in CliVar as Benign. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14152389-C-T is described in CliVar as Benign. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14152389-C-T is described in CliVar as Benign. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14152389-C-T is described in CliVar as Benign. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14152389-C-T is described in CliVar as Benign. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14152389-C-T is described in CliVar as Benign. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14152389-C-T is described in CliVar as Benign. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14152389-C-T is described in CliVar as Benign. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14152389-C-T is described in CliVar as Benign. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14152389-C-T is described in CliVar as Benign. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14152389-C-T is described in CliVar as Benign. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14152389-C-T is described in CliVar as Benign. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14152389-C-T is described in CliVar as Benign. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14152389-C-T is described in CliVar as Benign. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14152389-C-T is described in CliVar as Benign. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.36 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5 link	c.2061G>A	p.Arg687Arg	synonymous_variant	Exon 11 of 16	ENST00000285021.12	NP_004619.3	Q01831-1X5DRB1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12 link	c.2061G>A	p.Arg687Arg	synonymous_variant	Exon 11 of 16	1	NM_004628.5	ENSP00000285021.8		Q01831-1

Frequencies

GnomAD3 genomes

AF:

0.260

AC:

39500

AN:

151998

Hom.:

5321

Cov.:

show subpopulations

Gnomad AFR

AF:

0.300

Gnomad AMI

AF:

0.157

Gnomad AMR

AF:

0.258

Gnomad ASJ

AF:

0.228

Gnomad EAS

AF:

0.0418

Gnomad SAS

AF:

0.291

Gnomad FIN

AF:

0.220

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.259

Gnomad OTH

AF:

0.259

GnomAD2 exomes

AF:

0.253

AC:

62068

AN:

245744

AF XY:

0.251

show subpopulations

Gnomad AFR exome

AF:

0.305

Gnomad AMR exome

AF:

0.312

Gnomad ASJ exome

AF:

0.234

Gnomad EAS exome

AF:

0.0394

Gnomad FIN exome

AF:

0.229

Gnomad NFE exome

AF:

0.259

Gnomad OTH exome

AF:

0.240

GnomAD4 exome

AF:

0.261

AC:

381438

AN:

1459068

Hom.:

51627

Cov.:

AF XY:

0.261

AC XY:

189298

AN XY:

725600

show subpopulations

African (AFR)

AF:

0.309

AC:

10336

AN:

33410

American (AMR)

AF:

0.310

AC:

13759

AN:

44324

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

5943

AN:

26094

East Asian (EAS)

AF:

0.0387

AC:

1533

AN:

39644

South Asian (SAS)

AF:

0.286

AC:

24527

AN:

85770

European-Finnish (FIN)

AF:

0.228

AC:

12150

AN:

53260

Middle Eastern (MID)

AF:

0.207

AC:

1190

AN:

5760

European-Non Finnish (NFE)

AF:

0.267

AC:

296877

AN:

1110502

Other (OTH)

AF:

0.251

AC:

15123

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

13985

27970

41955

55940

69925

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9984

19968

29952

39936

49920

<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:

0.260

AC:

39546

AN:

152116

Hom.:

5328

Cov.:

AF XY:

0.258

AC XY:

19193

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.301

AC:

12474

AN:

41484

American (AMR)

AF:

0.258

AC:

3944

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

790

AN:

3472

East Asian (EAS)

AF:

0.0417

AC:

216

AN:

5182

South Asian (SAS)

AF:

0.291

AC:

1403

AN:

4818

European-Finnish (FIN)

AF:

0.220

AC:

2329

AN:

10596

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.259

AC:

17635

AN:

67964

Other (OTH)

AF:

0.257

AC:

543

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1507

3014

4520

6027

7534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

410

820

1230

1640

2050

<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:

0.265

Hom.:

3746

Bravo

AF:

0.265

Asia WGS

AF:

0.210

AC:

728

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum, group C

Benign:3

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 16, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: XPC c.2061G>A results in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.25 in 245744 control chromosomes in the gnomAD database, including 8333 homozygotes. The observed variant frequency is approximately 357 fold of the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma Pigmentosum phenotype (0.00071), strongly suggesting that the variant is benign. The variant c.2061G>A, has been reported in the literature (example: PMID: 27285993, 10766188). One ClinVar submitter (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Xeroderma pigmentosum group A

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=88/12

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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