rs2470458

Variant names:

• chr3-14145323-T-C
• rs2470458
• ENST00000608606.1:n.237T>C

Variant summary

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

The ENST00000608606.1(ENSG00000268279):​n.237T>C variant causes a splice region, non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 696,988 control chromosomes in the GnomAD database, including 12,019 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.17 (2414 hom., cov: 32)
  • Exomes 𝑓: 0.17 (9605 hom.)
• Consequence: ENSG00000268279 ENST00000608606.1 splice_region, non_coding_transcript_exon
• Scores: Splicing: ADA: 0.0001236
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.911
• Publications: 19 publications found

Genes affected

ENSG00000268279 (HGNC:):

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5	c.*618A>G		3_prime_UTR_variant	Exon 16 of 16	ENST00000285021.12	NP_004619.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000268279	ENST00000608606.1	n.237T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 5	5		ENSP00000476275.1
XPC	ENST00000285021.12	c.*618A>G		3_prime_UTR_variant	Exon 16 of 16	1	NM_004628.5	ENSP00000285021.8

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25259 AN: 151884 Hom.: 2414 Cov.: 32

Gnomad AFR AF: 0.0967

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0955

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.192

GnomAD2 exomes AF: 0.152 AC: 19308 AN: 127384 AF XY: 0.152

Gnomad AFR exome AF: 0.0912

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.000291

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.175 AC: 95254 AN: 544986 Hom.: 9605 Cov.: 0 AF XY: 0.173 AC XY: 50912 AN XY: 294966

African (AFR) AF: 0.0961 AC: 1495 AN: 15552

American (AMR) AF: 0.120 AC: 4102 AN: 34064

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 4014 AN: 19934

East Asian (EAS) AF: 0.000249 AC: 8 AN: 32078

South Asian (SAS) AF: 0.104 AC: 6397 AN: 61778

European-Finnish (FIN) AF: 0.233 AC: 7737 AN: 33164

Middle Eastern (MID) AF: 0.157 AC: 382 AN: 2430

European-Non Finnish (NFE) AF: 0.208 AC: 65735 AN: 315674

Other (OTH) AF: 0.178 AC: 5384 AN: 30312

GnomAD4 genome AF: 0.166 AC: 25259 AN: 152002 Hom.: 2414 Cov.: 32 AF XY: 0.164 AC XY: 12200 AN XY: 74290

African (AFR) AF: 0.0965 AC: 4005 AN: 41490

American (AMR) AF: 0.156 AC: 2379 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 723 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0960 AC: 462 AN: 4814

European-Finnish (FIN) AF: 0.238 AC: 2508 AN: 10528

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14412 AN: 67946

Other (OTH) AF: 0.190 AC: 400 AN: 2106

Alfa AF: 0.198 Hom.: 4023

Bravo AF: 0.157

Asia WGS AF: 0.0420 AC: 148 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Xeroderma pigmentosum, group C Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.0
DANN	Benign	0.64
PhyloP100		0.91
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.018
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: rs2470458; hg19: chr3-14186823;