NM_024422.6:c.96delC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_024422.6(DSC2):c.96delC(p.Cys32fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,448,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

DSC2
NM_024422.6 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:1

Conservation

PhyloP100: 0.550

Publications

2 publications found

Variant links:

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]

DSC2 Gene-Disease associations (from GenCC):

familial isolated arrhythmogenic right ventricular dysplasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
arrhythmogenic right ventricular dysplasia 11
Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
colorectal adenoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

DSC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 92 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 18-31093616-TG-T is Pathogenic according to our data. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204. Variant chr18-31093616-TG-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46204.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6 link	c.96delC	p.Cys32fs	frameshift_variant	Exon 2 of 16	ENST00000280904.11	NP_077740.1	Q02487-1
DSC2	NM_004949.5 link	c.96delC	p.Cys32fs	frameshift_variant	Exon 2 of 17		NP_004940.1	Q02487-2
DSC2	NM_001406506.1 link	c.-334delC		5_prime_UTR_variant	Exon 2 of 16		NP_001393435.1
DSC2	NM_001406507.1 link	c.-334delC		5_prime_UTR_variant	Exon 2 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11 link	c.96delC	p.Cys32fs	frameshift_variant	Exon 2 of 16	1	NM_024422.6	ENSP00000280904.6		Q02487-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1448060

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33206

American (AMR)

AF:

0.00

AC:

AN:

44448

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25610

East Asian (EAS)

AF:

0.00

AC:

AN:

39208

South Asian (SAS)

AF:

0.00

AC:

AN:

85358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00000363

AC:

AN:

1102814

Other (OTH)

AF:

0.00

AC:

AN:

59562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jun 13, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31402444, 23911551, 26743238, 19863551) -

Oct 05, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Pathogenic:2

Sep 26, 2024

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM2, PS4_supp -

Sep 14, 2023

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.96delC variant, located in coding exon 2 of the DSC2 gene, results from a deletion of one nucleotide at nucleotide position 96, causing a translational frameshift with a predicted alternate stop codon (p.C32*). The predicted stop codon occurs in the 5’ end of theDSC2 gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). Direct evidence for this alteration is unavailable, however premature termination codons are typically deleterious in nature. This variant has been detected in individuals from an arrhythmogenic right ventricular cardiomyopathy cohort (Adler A et al. Circ Arrhythm Electrophysiol, 2016 Jan;9:e003440). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Arrhythmogenic right ventricular dysplasia 11

Pathogenic:1

Jun 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Cys32*) 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 premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 19863551). ClinVar contains an entry for this variant (Variation ID: 46204). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy

Pathogenic:1

Jan 30, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:1

May 18, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

DSC2-related disorder

Pathogenic:1

Jan 31, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DSC2 c.96delC variant is predicted to result in premature protein termination (p.Cys32*). This variant has been reported in individuals with arrhythmogenic right ventricular dysplasia and cardiomyopathy (Barahona-Dussault et al. 2010. PubMed ID: 19863551; Ye et al. 2019. PubMed ID: 31402444). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Early termination variants in DSC2 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Familial isolated arrhythmogenic right ventricular dysplasia

Uncertain:1

Nov 20, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant changes 1 nucleotide in exon 2 of the DSC2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy/dysplasia who also harbored a different variant of uncertain significance in the same gene (PMID: 19863551), and in an individual suspected to be affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 26743238). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the clinical relevance of loss-of-function DSC2 truncation and splice variants in autosomal dominant arrhythmogenic cardiomyopathy is not yet clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.55

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over