rs777688726

Positions:

chr18-31082969-A-G

Variant summary

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

The NM_024422.6(DSC2):c.1034T>C(p.Ile345Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,540 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I345V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6

Conservation

PhyloP100: 7.66

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, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DSC2	NM_024422.6 linkuse as main transcript	c.1034T>C	p.Ile345Thr	missense_variant	8/16	ENST00000280904.11
DSC2	NM_004949.5 linkuse as main transcript	c.1034T>C	p.Ile345Thr	missense_variant	8/17
DSC2	NM_001406506.1 linkuse as main transcript	c.605T>C	p.Ile202Thr	missense_variant	8/16
DSC2	NM_001406507.1 linkuse as main transcript	c.605T>C	p.Ile202Thr	missense_variant	8/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11 linkuse as main transcript	c.1034T>C	p.Ile345Thr	missense_variant	8/16	1	NM_024422.6	P1	Q02487-1
DSC2	ENST00000251081.8 linkuse as main transcript	c.1034T>C	p.Ile345Thr	missense_variant	8/17	1			Q02487-2
DSC2	ENST00000648081.1 linkuse as main transcript	c.605T>C	p.Ile202Thr	missense_variant	9/17
DSC2	ENST00000682357.1 linkuse as main transcript	c.605T>C	p.Ile202Thr	missense_variant	8/16

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152268

Hom.:

Cov.:

show subpopulations

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251066

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135720

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461272

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726948

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74390

show subpopulations

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Klaassen Lab, Charite University Medicine Berlin

Jul 03, 2019

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 19, 2024

Variant summary: DSC2 c.1034T>C (p.Ile345Thr) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251066 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1034T>C has been reported in the literature in individuals affected with Arrhythmogenic cardiomyopathy (e.g. Goudal_2022), individuals affected or unaffected with Arrhythmogenic Right Ventricular Cardiomyopathy (e.g. Beffagna_2007, Christensen_ 2021), or pediatric cardiomyopathy with an additional reported DSG2 variant (e.g. Kuhnisch_2019), in all cases without evidence of causality. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. One publication reports experimental evidence evaluating an impact on protein function, showing the variant results in abberrant cytoplasmic localization away from cell membrane in cultured cardiomyocytes (e.g. Beffagna_2007), however, effect in disease remains unknown. The following publications have been ascertained in the context of this evaluation (PMID: 17963498, 34400560, 35819174, 28471438, 31568572). ClinVar contains an entry for this variant (Variation ID: 241471). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Arrhythmogenic right ventricular dysplasia 11

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 345 of the DSC2 protein (p.Ile345Thr). This variant is present in population databases (rs777688726, gnomAD 0.003%). This missense change has been observed in individual(s) with arrhythmogenic cardiomyopathy (PMID: 17963498, 28471438, 35819174). ClinVar contains an entry for this variant (Variation ID: 241471). 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 not expected to disrupt DSC2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects DSC2 function (PMID: 17963498). 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

May 18, 2023

This missense variant replaces isoleucine with threonine at codon 345 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 this variant affects the intracellular localization of the DSC2 protein (PMID: 17963498). This variant has been reported in two unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 17963498, 31568572). One of these individuals also carried a truncation variant in the DSG2 gene (PMID: 31568572). This variant has been identified in 2/251066 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 07, 2022

Reported in a pediatric patient with ARVC who also harbored a truncating variant in the DSG2 gene (Kuhnisch et al., 2019), although no informative segregation data are available; Also observed in 16 individuals from a cohort of 30,716 individuals who underwent exome sequencing, and none of these individuals had a diagnosis of ARVC based on review of existing electronic health records (Haggerty et al., 2017); Expression studies in neonatal rat cardiomyocytes and cultured mouse cardiac muscle cells (HL-1 cells) suggest that I345T may impact proper cellular localization of desmocollin-2 protein (Beffagna et al., 2007); however, the clinical validity of these studies remains to be determined; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17963498, 20197793, 24070718, 26310507, 26138720, 28471438, 31333075, 31568572, 31402444, 32466575) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2020

The p.I345T variant (also known as c.1034T>C), located in coding exon 8 of the DSC2 gene, results from a T to C substitution at nucleotide position 1034. The isoleucine at codon 345 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in arrhythmogenic right ventricular cardiomyopathy (ARVC) and pediatric cardiomyopathy cohorts (Beffagna G et al. BMC Med. Genet. 2007;8:65; Kühnisch J et al. Clin. Genet., 2019 Dec;96:549-559). In vitro studies have suggested that this variant alters the localization of the DSC2 protein; however, the clinical significance of this mislocalization is uncertain (Beffagna G et al. BMC Med. Genet. 2007;8:65). This amino acid position is not well 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

Jan 11, 2024

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.58

T;T;T

M_CAP

Benign

0.060

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.0088

MutationAssessor

Pathogenic

3.2

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.3

D;D;.

REVEL

Uncertain

0.51

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.0070

D;D;.

Polyphen

0.87

P;P;.

Vest4

0.95

MutPred

0.94

Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);.;

MVP

0.83

MPC

0.41

ClinPred

0.97

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.68

gMVP

0.83

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

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