rs1893963

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024422.6(DSC2):c.2326A>G(p.Ile776Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,930 control chromosomes in the GnomAD database, including 12,799 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I776M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.18 ( 3924 hom., cov: 32)

Exomes 𝑓: 0.096 ( 8875 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.0600

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.502965E-4).

BP6

Variant 18-31069076-T-C is Benign according to our data. Variant chr18-31069076-T-C is described in ClinVar as [Benign]. Clinvar id is 46178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31069076-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DSC2	NM_024422.6 linkuse as main transcript	c.2326A>G	p.Ile776Val	missense_variant	15/16	ENST00000280904.11
DSC2	NM_004949.5 linkuse as main transcript	c.2326A>G	p.Ile776Val	missense_variant	15/17
DSC2	NM_001406506.1 linkuse as main transcript	c.1897A>G	p.Ile633Val	missense_variant	15/16
DSC2	NM_001406507.1 linkuse as main transcript	c.1897A>G	p.Ile633Val	missense_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11 linkuse as main transcript	c.2326A>G	p.Ile776Val	missense_variant	15/16	1	NM_024422.6	P1	Q02487-1
DSC2	ENST00000251081.8 linkuse as main transcript	c.2326A>G	p.Ile776Val	missense_variant	15/17	1			Q02487-2
DSC2	ENST00000648081.1 linkuse as main transcript	c.1897A>G	p.Ile633Val	missense_variant	16/17
DSC2	ENST00000682357.1 linkuse as main transcript	c.1897A>G	p.Ile633Val	missense_variant	15/16

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26841

AN:

151972

Hom.:

3899

Cov.:

show subpopulations

Gnomad AFR

AF:

0.400

Gnomad AMI

AF:

0.127

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.0971

Gnomad EAS

AF:

0.0961

Gnomad SAS

AF:

0.0701

Gnomad FIN

AF:

0.0531

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0857

Gnomad OTH

AF:

0.139

GnomAD3 exomes

AF:

0.116

AC:

29026

AN:

251110

Hom.:

2726

AF XY:

0.105

AC XY:

14215

AN XY:

135706

show subpopulations

Gnomad AFR exome

AF:

0.416

Gnomad AMR exome

AF:

0.176

Gnomad ASJ exome

AF:

0.100

Gnomad EAS exome

AF:

0.100

Gnomad SAS exome

AF:

0.0670

Gnomad FIN exome

AF:

0.0578

Gnomad NFE exome

AF:

0.0835

Gnomad OTH exome

AF:

0.0908

GnomAD4 exome

AF:

0.0955

AC:

139653

AN:

1461840

Hom.:

8875

Cov.:

AF XY:

0.0929

AC XY:

67592

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.410

Gnomad4 AMR exome

AF:

0.175

Gnomad4 ASJ exome

AF:

0.102

Gnomad4 EAS exome

AF:

0.0928

Gnomad4 SAS exome

AF:

0.0660

Gnomad4 FIN exome

AF:

0.0598

Gnomad4 NFE exome

AF:

0.0864

Gnomad4 OTH exome

AF:

0.102

GnomAD4 genome

AF:

0.177

AC:

26926

AN:

152090

Hom.:

3924

Cov.:

AF XY:

0.175

AC XY:

13018

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.400

Gnomad4 AMR

AF:

0.153

Gnomad4 ASJ

AF:

0.0971

Gnomad4 EAS

AF:

0.0959

Gnomad4 SAS

AF:

0.0701

Gnomad4 FIN

AF:

0.0531

Gnomad4 NFE

AF:

0.0857

Gnomad4 OTH

AF:

0.139

Alfa

AF:

0.100

Hom.:

2883

Bravo

AF:

0.196

TwinsUK

AF:

0.0874

AC:

324

ALSPAC

AF:

0.0861

AC:

332

ESP6500AA

AF:

0.401

AC:

1767

ESP6500EA

AF:

0.0837

AC:

720

ExAC

AF:

0.119

AC:

14439

Asia WGS

AF:

0.124

AC:

432

AN:

3478

EpiCase

AF:

0.0814

EpiControl

AF:

0.0739

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 29, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2007	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Arrhythmogenic right ventricular dysplasia 11

Benign:5

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

Cardiomyopathy

Benign:2

Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 19, 2018	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 27153395, 19863551, 25445213) -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2015

This alteration is classified as 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. -

Familial isolated arrhythmogenic right ventricular dysplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

Cadd

Benign

0.19

Dann

Benign

0.59

DEOGEN2

Benign

0.045

T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0023

LIST_S2

Benign

0.042

T;T;T

MetaRNN

Benign

0.00035

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.8

N;N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.32

PROVEAN

Benign

0.18

N;N;.

REVEL

Benign

0.10

Sift

Benign

1.0

T;T;.

Sift4G

Benign

1.0

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.019

MPC

0.063

ClinPred

0.00087

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.024

gMVP

0.17

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