rs2228000

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004628.5(XPC):c.1496C>T(p.Ala499Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,613,464 control chromosomes in the GnomAD database, including 50,315 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A499T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.22 ( 4131 hom., cov: 32)

Exomes 𝑓: 0.25 ( 46184 hom. )

Consequence

XPC
NM_004628.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.00600

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002342701).

BP6

Variant 3-14158387-G-A is Benign according to our data. Variant chr3-14158387-G-A is described in ClinVar as [Benign]. Clinvar id is 135485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5 link	c.1496C>T	p.Ala499Val	missense_variant	Exon 9 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.1496C>T	p.Ala499Val	missense_variant	Exon 9 of 16	1	NM_004628.5	ENSP00000285021.8		Q01831-1

Frequencies

GnomAD3 genomes

AF:

0.215

AC:

32678

AN:

151730

Hom.:

4135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0912

Gnomad AMI

AF:

0.444

Gnomad AMR

AF:

0.241

Gnomad ASJ

AF:

0.222

Gnomad EAS

AF:

0.364

Gnomad SAS

AF:

0.199

Gnomad FIN

AF:

0.367

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.247

Gnomad OTH

AF:

0.245

GnomAD3 exomes

AF:

0.244

AC:

60666

AN:

249122

Hom.:

7936

AF XY:

0.243

AC XY:

32906

AN XY:

135152

show subpopulations

Gnomad AFR exome

AF:

0.0899

Gnomad AMR exome

AF:

0.223

Gnomad ASJ exome

AF:

0.212

Gnomad EAS exome

AF:

0.361

Gnomad SAS exome

AF:

0.198

Gnomad FIN exome

AF:

0.356

Gnomad NFE exome

AF:

0.245

Gnomad OTH exome

AF:

0.251

GnomAD4 exome

AF:

0.247

AC:

360862

AN:

1461616

Hom.:

46184

Cov.:

AF XY:

0.246

AC XY:

178638

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.0806

Gnomad4 AMR exome

AF:

0.225

Gnomad4 ASJ exome

AF:

0.218

Gnomad4 EAS exome

AF:

0.345

Gnomad4 SAS exome

AF:

0.198

Gnomad4 FIN exome

AF:

0.349

Gnomad4 NFE exome

AF:

0.250

Gnomad4 OTH exome

AF:

0.239

GnomAD4 genome

AF:

0.215

AC:

32687

AN:

151848

Hom.:

4131

Cov.:

AF XY:

0.220

AC XY:

16344

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.0911

Gnomad4 AMR

AF:

0.241

Gnomad4 ASJ

AF:

0.222

Gnomad4 EAS

AF:

0.364

Gnomad4 SAS

AF:

0.200

Gnomad4 FIN

AF:

0.367

Gnomad4 NFE

AF:

0.247

Gnomad4 OTH

AF:

0.244

Alfa

AF:

0.242

Hom.:

9175

Bravo

AF:

0.202

TwinsUK

AF:

0.248

AC:

918

ALSPAC

AF:

0.250

AC:

965

ESP6500AA

AF:

0.0918

AC:

288

ESP6500EA

AF:

0.248

AC:

1778

ExAC

AF:

0.237

AC:

28666

Asia WGS

AF:

0.236

AC:

820

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 26, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26001739, 23436679, 27153395, 15700316, 20369554, 20193233, 24728327, 23400628, 17575242, 21113018, 19706757, 17882560) -

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

- -

Xeroderma pigmentosum, group C

Benign:3

Mar 06, 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. -

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

- -

not specified

Benign:2Other:1

Aug 27, 2018

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.1496C>T (p.Ala499Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.24 in 276928 control chromosomes in the gnomAD database, including 8807 homozygotes. The observed variant frequency is approximately 171-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma Pigmentosum phenotype (0.0014), strongly suggesting that the variant is benign. The variant has been indicated to be associated with an increased risk of cancer (He_2013). A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

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

- -

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

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

1.1

DANN

Benign

0.86

DEOGEN2

Benign

0.094

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.96

REVEL

Benign

0.012

Sift

Benign

0.33

Sift4G

Benign

0.17

Polyphen

0.0040

Vest4

0.019

MPC

0.12

ClinPred

0.00058

GERP RS

-1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.017

gMVP

0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over