rs1395367133

chr18-31101936-TCC-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_024422.6(DSC2):c.34_35del(p.Gly12SerfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000262 in 1,529,506 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G12G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: DSC2 NM_024422.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 0.476

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]

DSCAS (HGNC:51116): (DSC1/DSC2 antisense RNA)

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 74 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-31101936-TCC-T is Pathogenic according to our data. Variant chr18-31101936-TCC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 503979.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.34_35del	p.Gly12SerfsTer18	frameshift_variant	1/16	ENST00000280904.11
DSCAS	NR_110785.1	n.136+214_136+215del		intron_variant, non_coding_transcript_variant
DSC2	NM_004949.5	c.34_35del	p.Gly12SerfsTer18	frameshift_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.34_35del	p.Gly12SerfsTer18	frameshift_variant	1/16	1	NM_024422.6	P1
DSCAS	ENST00000581836.2	n.152+214_152+215del		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151820 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000218 AC: 3 AN: 1377686 Hom.: 0 AF XY: 0.00000294 AC XY: 2 AN XY: 679758

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151820 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74132

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change creates a premature translational stop signal (p.Gly12Serfs*18) in the DSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSC2 are known to be pathogenic (PMID: 23911551). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 503979). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 27, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 24, 2018

Although the c.34_35delGG pathogenic variant in the DSC2 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon glycine 12, changing it to a serine, and creating a premature stop codon at position 18 of the new reading frame, denoted p.Gly12SerfsX18. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple other downstream frameshift variants in the DSC2 gene have been reported in Human Gene Mutation Database in association with ARVC (Stenson et al., 2014), in a gene for which loss-of-function is a known mechanism of disease. Furthermore, the c.34_35delGG variant has not been observed in large population cohorts (Lek et al., 2016). -

Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 09, 2023

This variant encodes a premature stop of translation that is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. However, loss of function is not an established mechanism of disease in arrhythmogenic cardiomyopathy (PMID: 23863954, 18957847, 19863551, 23911551). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -

Computational scores

Source: dbNSFP v4.3

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: rs1395367133; hg19: chr18-28681899;