NM_024422.6:c.286A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_024422.6(DSC2):c.286A>G(p.Ile96Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,488 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I96T) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 0.998

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-31092168-A-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.1698404).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6 link	c.286A>G	p.Ile96Val	missense_variant	Exon 3 of 16	ENST00000280904.11	NP_077740.1	Q02487-1
DSC2	NM_004949.5 link	c.286A>G	p.Ile96Val	missense_variant	Exon 3 of 17		NP_004940.1	Q02487-2
DSC2	NM_001406506.1 link	c.-144A>G		5_prime_UTR_variant	Exon 3 of 16		NP_001393435.1
DSC2	NM_001406507.1 link	c.-144A>G		5_prime_UTR_variant	Exon 3 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DSC2	ENST00000280904.11 link	c.286A>G	p.Ile96Val	missense_variant	Exon 3 of 16	1	NM_024422.6	ENSP00000280904.6	Q02487-1
DSC2	ENST00000251081.8 link	c.286A>G	p.Ile96Val	missense_variant	Exon 3 of 17	1		ENSP00000251081.6	Q02487-2
DSC2	ENST00000648081.1 link	c.-181A>G		5_prime_UTR_variant	Exon 3 of 17			ENSP00000497441.1	A0A3B3ISU0
DSC2	ENST00000682357.1 link	c.-144A>G		5_prime_UTR_variant	Exon 3 of 16			ENSP00000507826.1	A0A3B3ISU0

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250806

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135560

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461290

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

726910

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000330

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11

Uncertain:2

Sep 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 96 of the DSC2 protein (p.Ile96Val). This variant is present in population databases (rs772447450, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 410656). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DSC2 protein function with a negative predictive value of 80%. 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

Sep 16, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DSC2 c.286A>G (p.Ile96Val) results in a conservative amino acid change located in the Cadherin prodomain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250806 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.286A>G in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 410656). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiomyopathy

Uncertain:1

Mar 07, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces isoleucine with valine at codon 96 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 hypertrophic cardiomyopathy (PMID: 30847666). This variant has been identified in 5/250806 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

Jun 05, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with cardiomyopathy in published literature; however, detailed clinical information was not provided (van Lint et al., 2019); This variant is associated with the following publications: (PMID: 30847666) -

Cardiovascular phenotype

Uncertain:1

Jun 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I96V variant (also known as c.286A>G), located in coding exon 3 of the DSC2 gene, results from an A to G substitution at nucleotide position 286. The isoleucine at codon 96 is replaced by valine, an amino acid with highly similar properties. This variant was detected in a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces isoleucine with valine at codon 96 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/250806 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.048

T;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.55

N;N

REVEL

Benign

0.14

Sift

Benign

0.37

T;T

Sift4G

Benign

0.17

T;D

Polyphen

0.72

P;P

Vest4

0.24

MVP

0.32

MPC

0.078

ClinPred

0.38

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.030

gMVP

0.28

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