Genetic Variant XPC:p.Arg240Gly (chr3-14165489-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004628.5(XPC):c.718C>G(p.Arg240Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,194 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R240C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

XPC
NM_004628.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.24

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004628.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
XPC	NM_004628.5	MANE Select	c.718C>G	p.Arg240Gly	missense	Exon 6 of 16	NP_004619.3
XPC	NM_001354727.2		c.718C>G	p.Arg240Gly	missense	Exon 6 of 16	NP_001341656.1
XPC	NM_001354729.2		c.700C>G	p.Arg234Gly	missense	Exon 6 of 16	NP_001341658.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
XPC	ENST00000285021.12	TSL:1 MANE Select	c.718C>G	p.Arg240Gly	missense	Exon 6 of 16	ENSP00000285021.8
XPC	ENST00000476581.6	TSL:1	n.*171C>G		non_coding_transcript_exon	Exon 5 of 15	ENSP00000424548.1
XPC	ENST00000476581.6	TSL:1	n.*171C>G		3_prime_UTR	Exon 5 of 15	ENSP00000424548.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000420

AC:

AN:

238244

AF XY:

0.00000777

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455194

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723046

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.00

AC:

AN:

43748

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25986

East Asian (EAS)

AF:

0.00

AC:

AN:

39528

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108836

Other (OTH)

AF:

0.00

AC:

AN:

60202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PhyloP100

4.2

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.15

Sift

Uncertain

0.013

Sift4G

Uncertain

0.022

Polyphen

0.42

Vest4

0.44

MutPred

0.73

Loss of stability (P = 0.0339)

MVP

0.21

MPC

0.20

ClinPred

0.57

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.27

gMVP

0.29

Mutation Taster

=90/10

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over