rs762556795

Positions:

chr18-31101968-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000280904.11(DSC2):c.4G>A(p.Glu2Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000728 in 1,524,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

DSC2
ENST00000280904.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 3.94

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:

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

DSCAS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09751704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSC2	NM_024422.6 linkuse as main transcript	c.4G>A	p.Glu2Lys	missense_variant	1/16	ENST00000280904.11	NP_077740.1
DSCAS	NR_110785.1 linkuse as main transcript	n.136+245C>T		intron_variant, non_coding_transcript_variant
DSC2	NM_004949.5 linkuse as main transcript	c.4G>A	p.Glu2Lys	missense_variant	1/17		NP_004940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11 linkuse as main transcript	c.4G>A	p.Glu2Lys	missense_variant	1/16	1	NM_024422.6	ENSP00000280904	P1	Q02487-1
DSCAS	ENST00000581836.2 linkuse as main transcript	n.152+245C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

118124

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

65148

show subpopulations

Gnomad AFR exome

AF:

0.000245

Gnomad AMR exome

AF:

0.0000441

Gnomad ASJ exome

AF:

0.000259

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000228

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000729

AC:

100

AN:

1372118

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

676542

show subpopulations

Gnomad4 AFR exome

AF:

0.0000334

Gnomad4 AMR exome

AF:

0.0000287

Gnomad4 ASJ exome

AF:

0.000121

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000810

Gnomad4 OTH exome

AF:

0.000122

GnomAD4 genome

AF:

0.0000724

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.000208

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2 of the DSC2 protein (p.Glu2Lys). This variant is present in population databases (rs762556795, gnomAD 0.03%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495). ClinVar contains an entry for this variant (Variation ID: 199776). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 05, 2018

The p.Glu2Lys variant (rs762556795) was reported in one patient with palpitation at 15 years age of onset without a family history (Christensen 2010). This variant is listed in the Genome Aggregation Database (gnomAD) with a population frequency of 0.02 percent in the European Non-Finnish population (identified on 12 out of 56,600 chromosomes) and has been reported to the ClinVar database (Variation ID: 199776). The glutamic acid at the second codon is weakly conserved and before the signal peptide which is cleaved off before insertion into the plasma membrane. Computational analyses of the p.Glu2Lys variant on protein structure and function provide conflicting results (SIFT: damaging, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Glu2Lys variant with certainty. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 03, 2023

This missense variant replaces glutamic acid with lysine at codon 2 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 26264440). This variant has been identified in 16/149434 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

Dec 29, 2023

Reported in one Danish individual fulfilling task force criteria for a diagnosis of ARVC (PMID: 20864495); Identified in 15 individuals from a cohort of 30,716 predominantly European individuals undergoing exome sequencing and review of available electronic health records indicated that none of these individuals had a documented diagnosis of ARVC (PMID: 28471438), although specific clinical details and follow-up cardiac evaluations were not reported; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23911551, 26264440, 20864495, 31402444, 28471438) -

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

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.047

T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.062

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.36

T;T

M_CAP

Benign

0.061

MetaRNN

Benign

0.098

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.11

N;N

REVEL

Benign

0.26

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.060

T;T

Polyphen

0.0

B;B

Vest4

0.67

MutPred

0.29

Gain of MoRF binding (P = 0.0071);Gain of MoRF binding (P = 0.0071);

MVP

0.65

MPC

0.082

ClinPred

0.12

GERP RS

3.7

Varity_R

0.16

gMVP

0.76

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