18-31066778-C-T

Position:

• chr18-31066778-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_024422.6(DSC2):​c.*1237G>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 0.00276 in 152,160 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 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: -0.0940

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00276 (420/152160) while in subpopulation AFR AF= 0.00934 (388/41532). AF 95% confidence interval is 0.00858. There are 1 homozygotes in gnomad4. There are 211 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.*1237G>A		3_prime_UTR_variant	16/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.*1445G>A		3_prime_UTR_variant	17/17		NP_004940.1
DSC2	NM_001406506.1	c.*1237G>A		3_prime_UTR_variant	16/16		NP_001393435.1
DSC2	NM_001406507.1	c.*1445G>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.*1237G>A		3_prime_UTR_variant	16/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081	c.*1445G>A		3_prime_UTR_variant	17/17	1		ENSP00000251081.6
DSC2	ENST00000648081	c.*1237G>A		3_prime_UTR_variant	17/17			ENSP00000497441.1
DSC2	ENST00000682357	c.*1237G>A		3_prime_UTR_variant	16/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 417 AN: 152042 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00930

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00431

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: 0.00276 AC: 420 AN: 152160 Hom.: 1 Cov.: 32 AF XY: 0.00284 AC XY: 211 AN XY: 74386

Gnomad4 AFR AF: 0.00934

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00236 Hom.: 0

Bravo AF: 0.00329

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.3
DANN	Benign	0.65

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: rs28530723; hg19: chr18-28646744;