rs727504578

Positions:

chr18-31091108-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_024422.6(DSC2):c.394C>T(p.Arg132Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 3.77

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DSC2	NM_024422.6 linkuse as main transcript	c.394C>T	p.Arg132Cys	missense_variant	4/16	ENST00000280904.11
DSC2	NM_004949.5 linkuse as main transcript	c.394C>T	p.Arg132Cys	missense_variant	4/17
DSC2	NM_001406506.1 linkuse as main transcript	c.-36C>T		5_prime_UTR_variant	4/16
DSC2	NM_001406507.1 linkuse as main transcript	c.-36C>T		5_prime_UTR_variant	4/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11 linkuse as main transcript	c.394C>T	p.Arg132Cys	missense_variant	4/16	1	NM_024422.6	P1	Q02487-1
DSC2	ENST00000251081.8 linkuse as main transcript	c.394C>T	p.Arg132Cys	missense_variant	4/17	1			Q02487-2
DSC2	ENST00000648081.1 linkuse as main transcript	c.-36C>T		5_prime_UTR_variant	5/17
DSC2	ENST00000682357.1 linkuse as main transcript	c.-36C>T		5_prime_UTR_variant	4/16

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251182

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461732

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000104

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 24, 2018

The p.Arg132Cys variant in DSC2 has been identified in 3 individuals with ARVC, one of whom carried a likely pathogenic variant in PKP2 and another of whom also carried a frameshift variant in DSC2 (Fressart 2010, Ohno 2013, Wada 2017, LMM data). This variant has been identified in 10/282564 chromosomes by the gnomAD ( http://gnomad.broadinstitute.org). Computational prediction tools and conservati on analysis suggest that the p.Arg132Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary , the clinical significance of the p.Arg132Cys variant is uncertain. ACMG/AMP Cr iteria applied: PP3. -

Arrhythmogenic right ventricular dysplasia 11

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 132 of the DSC2 protein (p.Arg132Cys). This variant is present in population databases (rs727504578, gnomAD 0.02%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 23514727, 33784018). ClinVar contains an entry for this variant (Variation ID: 178972). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DSC2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DSC2 function (PMID: 33784018). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 16, 2022

This missense variant replaces arginine with cysteine at codon 132 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that, unlike wildtype, this variant can't rescue the cardiovascular phenotypes in DSC2 knockdown zebrafish model (PMID: 33784018). This variant has been reported in an individual affected with cardiac arrest (ClinVar SCV001245073.1) and in four unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 20400443, 23514727, 29178656, 33784018, ClinVar SCV000205460.4). Two of these probands also carried a truncating variant in DSC2 or PKP2 genes (PMID: 20400443, ClinVar SCV001245073.1). Studies with heart samples and cardiomyocytes derived from one of the probands revealed altered electric activity and a marked reduction of DSC2 in both mRNA and protein levels (PMID: 33784018, 35297182). This variant has been identified in 10/282564 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

Aborted sudden cardiac death

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Jul 26, 2018

DSC2 Arg132Cys has been reported previously in 2 ARVC patients, however both patients also had other DSC2 variants (Fressart V et al., 2010; Ohno S, et al., 2013). We have identified this variant in a proband of south-east asian descent whom presented with cardiac arrest. The patient was also found to have a second variant (PKP2 p.Leu744Serfs*3). Clinical screening did not uncover any abnormal findings, but it is possible that the patient may have a 'concealed' ARVC phenotype. The proband has no family history of any inherited cardiac disease or sudden death. The variant is present at an elevated frequency in the Genome Aggregation Database (MAF= 0.000036, http://gnomad.broadinstitute.org/). In silico tools SIFT, MutationTaster, CADD and PolyPhen-2 all predict the variant to be deleterious. In summary, the variant has been reported in at least 3 probands with multiple variants, it is present in population databases but is still considered rare and in silico tools predict it to be deleterious, therefore based on this conflicting information we classify DSC2 Arg132Cys as a variant of 'uncertain significance'. -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University

Jun 01, 2023

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2019

The p.R132C variant (also known as c.394C>T), located in coding exon 4 of the DSC2 gene, results from a C to T substitution at nucleotide position 394. The arginine at codon 132 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), who also had additional cardiac-related variants detected (Fressart V et al. Europace, 2010 Jun;12:861-8; Ohno S et al. Circ. J., 2013 Mar;77:1534-42). This alteration has also been seen in an exome cohort, but detailed cardiovascular history was not provided (Haggerty CM et al. Genet. Med., 2017 11;19:1245-1252). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Dec 18, 2023

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;.

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

-0.058

MutationAssessor

Pathogenic

3.7

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.91

MutPred

0.93

Loss of disorder (P = 0.0268);Loss of disorder (P = 0.0268);

MVP

0.73

MPC

0.50

ClinPred

0.84

GERP RS

3.9

Varity_R

0.27

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over