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GeneBe

rs2228000

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. 13/19 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

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O: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-AS1 (HGNC:55014): (XPC antisense RNA 1)

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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/exons MANE UniProt
XPCNM_004628.5 linkuse as main transcriptc.1496C>T p.Ala499Val missense_variant 9/16 ENST00000285021.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
XPCENST00000285021.12 linkuse as main transcriptc.1496C>T p.Ala499Val missense_variant 9/161 NM_004628.5 P1Q01831-1
XPC-AS1ENST00000627116.2 linkuse as main transcriptn.457-7489G>A intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.215
AC:
32678
AN:
151730
Hom.:
4135
Cov.:
32
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.:
35
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.:
32
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:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2Other:1
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 27, 2018Variant 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. -
not provided, no classification providedreference populationITMISep 19, 2013- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Xeroderma pigmentosum, group C Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This 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. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxFeb 26, 2019This variant is associated with the following publications: (PMID: 26001739, 23436679, 27153395, 15700316, 20369554, 20193233, 24728327, 23400628, 17575242, 21113018, 19706757, 17882560) -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Xeroderma pigmentosum group A Benign:1
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.67
T
BayesDel_noAF
Benign
-0.59
Cadd
Benign
1.1
Dann
Benign
0.86
DEOGEN2
Benign
0.094
T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.32
N
LIST_S2
Benign
0.44
T
MetaRNN
Benign
0.0023
T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
1.0
P;P
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.96
N
REVEL
Benign
0.012
Sift
Benign
0.33
T
Sift4G
Benign
0.17
T
Polyphen
0.0040
B
Vest4
0.019
MPC
0.12
ClinPred
0.00058
T
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.

Other links and lift over

dbSNP: rs2228000; hg19: chr3-14199887; COSMIC: COSV53203534; COSMIC: COSV53203534; API