18-31066357-C-T

Position:

• chr18-31066357-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_024422.6(DSC2):​c.*1658G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00457 in 152,204 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (2 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: DSC2 NM_024422.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.132

Genes affected

DSC2 (HGNC:3036): (desmocollin 2) This gene encodes a member of the desmocollin protein subfamily. Desmocollins, along with desmogleins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmocollin family members on chromosome 18. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia-11, and reduced protein expression has been described in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00457 (695/152204) while in subpopulation AMR AF= 0.00739 (113/15282). AF 95% confidence interval is 0.00638. There are 2 homozygotes in gnomad4. There are 328 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.*1658G>A		3_prime_UTR_variant	16/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.*1866G>A		3_prime_UTR_variant	17/17		NP_004940.1
DSC2	NM_001406506.1	c.*1658G>A		3_prime_UTR_variant	16/16		NP_001393435.1
DSC2	NM_001406507.1	c.*1866G>A		3_prime_UTR_variant	17/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904	c.*1658G>A		3_prime_UTR_variant	16/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081	c.*1866G>A		3_prime_UTR_variant	17/17	1		ENSP00000251081.6
DSC2	ENST00000648081	c.*1658G>A		3_prime_UTR_variant	17/17			ENSP00000497441.1
DSC2	ENST00000682357	c.*1658G>A		3_prime_UTR_variant	16/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes AF: 0.00458 AC: 696 AN: 152086 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00690

Gnomad OTH AF: 0.00430

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.00457 AC: 695 AN: 152204 Hom.: 2 Cov.: 32 AF XY: 0.00441 AC XY: 328 AN XY: 74384

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00142

Gnomad4 NFE AF: 0.00690

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00529 Hom.: 0

Bravo AF: 0.00535

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.69

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

Other links and lift over

dbSNP: rs185216732; hg19: chr18-28646323;