rs2229089

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004628.5(XPC):c.142C>T(p.Leu48Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0272 in 1,606,840 control chromosomes in the GnomAD database, including 738 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 48 hom., cov: 32)

Exomes 𝑓: 0.028 ( 690 hom. )

Consequence

XPC
NM_004628.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 0.240

Publications

18 publications found

Variant links:

COSMIC-nc: COSV53208173

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 Gene-Disease associations (from GenCC):

xeroderma pigmentosum group C
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Myriad Women’s Health, Genomics England PanelApp
xeroderma pigmentosum
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

XPC 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=0.0023067892).

BP6

Variant 3-14173024-G-A is Benign according to our data. Variant chr3-14173024-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0212 (3225/152266) while in subpopulation NFE AF = 0.0287 (1949/68008). AF 95% confidence interval is 0.0276. There are 48 homozygotes in GnomAd4. There are 1657 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5 link	c.142C>T	p.Leu48Phe	missense_variant	Exon 2 of 16	ENST00000285021.12	NP_004619.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12 link	c.142C>T	p.Leu48Phe	missense_variant	Exon 2 of 16	1	NM_004628.5	ENSP00000285021.8

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3225

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00490

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.0172

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0151

Gnomad FIN

AF:

0.0586

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0287

Gnomad OTH

AF:

0.0191

GnomAD2 exomes

AF:

0.0215

AC:

5095

AN:

236852

AF XY:

0.0224

show subpopulations

Gnomad AFR exome

AF:

0.00438

Gnomad AMR exome

AF:

0.00894

Gnomad ASJ exome

AF:

0.00537

Gnomad EAS exome

AF:

0.000175

Gnomad FIN exome

AF:

0.0564

Gnomad NFE exome

AF:

0.0279

Gnomad OTH exome

AF:

0.0206

GnomAD4 exome

AF:

0.0278

AC:

40465

AN:

1454574

Hom.:

690

Cov.:

AF XY:

0.0276

AC XY:

19937

AN XY:

723250

show subpopulations

African (AFR)

AF:

0.00366

AC:

121

AN:

33026

American (AMR)

AF:

0.00956

AC:

414

AN:

43326

Ashkenazi Jewish (ASJ)

AF:

0.00552

AC:

143

AN:

25886

East Asian (EAS)

AF:

0.000101

AC:

AN:

39654

South Asian (SAS)

AF:

0.0140

AC:

1195

AN:

85102

European-Finnish (FIN)

AF:

0.0532

AC:

2826

AN:

53136

Middle Eastern (MID)

AF:

0.00853

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0309

AC:

34302

AN:

1108660

Other (OTH)

AF:

0.0235

AC:

1411

AN:

60040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

2113

4226

6338

8451

10564

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1284

2568

3852

5136

6420

<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:

0.0212

AC:

3225

AN:

152266

Hom.:

Cov.:

AF XY:

0.0223

AC XY:

1657

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00488

AC:

203

AN:

41566

American (AMR)

AF:

0.0172

AC:

263

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.000771

AC:

AN:

5188

South Asian (SAS)

AF:

0.0156

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0586

AC:

621

AN:

10598

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0287

AC:

1949

AN:

68008

Other (OTH)

AF:

0.0189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

166

332

498

664

830

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0243

Hom.:

203

Bravo

AF:

0.0175

TwinsUK

AF:

0.0329

AC:

122

ALSPAC

AF:

0.0327

AC:

126

ESP6500AA

AF:

0.00506

AC:

ESP6500EA

AF:

0.0287

AC:

236

ExAC

AF:

0.0201

AC:

2424

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 11, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28146470)

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Xeroderma pigmentosum, group C

Benign:3

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 05, 2021

Genome-Nilou Lab

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 specified

Benign:2Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 10, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Xeroderma pigmentosum group A

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

5.6

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.45

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.

PhyloP100

0.24

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.093

Sift

Benign

0.73

T;T

Sift4G

Benign

0.70

T;T

Vest4

0.026

ClinPred

0.00073

GERP RS

1.0

Varity_R

0.019

gMVP

0.030

Mutation Taster

=97/3

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