rs2607755

Variant names:

• chr3-14172533-T-C
• rs2607755
• NM_004628.5:c.299+334A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004628.5(XPC):​c.299+334A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 152,040 control chromosomes in the GnomAD database, including 13,681 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (13681 hom., cov: 32)
• Consequence: XPC NM_004628.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.583
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5	c.299+334A>G		intron_variant	Intron 2 of 15	ENST00000285021.12	NP_004619.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12	c.299+334A>G		intron_variant	Intron 2 of 15	1	NM_004628.5	ENSP00000285021.8

Frequencies

GnomAD3 genomes AF: 0.415 AC: 62983 AN: 151920 Hom.: 13672 Cov.: 32

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.0426

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.472

Gnomad OTH AF: 0.445

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.415 AC: 63031 AN: 152040 Hom.: 13681 Cov.: 32 AF XY: 0.412 AC XY: 30602 AN XY: 74322

African (AFR) AF: 0.354 AC: 14695 AN: 41456

American (AMR) AF: 0.411 AC: 6282 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1477 AN: 3470

East Asian (EAS) AF: 0.0425 AC: 220 AN: 5178

South Asian (SAS) AF: 0.387 AC: 1867 AN: 4826

European-Finnish (FIN) AF: 0.462 AC: 4879 AN: 10554

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.472 AC: 32100 AN: 67954

Other (OTH) AF: 0.440 AC: 931 AN: 2114

Alfa AF: 0.439 Hom.: 1913

Bravo AF: 0.409

Asia WGS AF: 0.251 AC: 870 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.18
DANN	Benign	0.24
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2607755; hg19: chr3-14214033;