rs147109895

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_ModerateBP6BS1

The NM_024422.6(DSC2):c.2587G>A(p.Gly863Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000555 in 1,614,050 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 1 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:2

Conservation

PhyloP100: 6.72

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_benign. Variant got -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19868788).

BP6

Variant 18-31068134-C-T is Benign according to our data. Variant chr18-31068134-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46183.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}. Variant chr18-31068134-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000223 (34/152236) while in subpopulation NFE AF= 0.000323 (22/68018). AF 95% confidence interval is 0.000218. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6 link	c.2587G>A	p.Gly863Arg	missense_variant	Exon 16 of 16	ENST00000280904.11	NP_077740.1	Q02487-1
DSC2	NM_001406506.1 link	c.2158G>A	p.Gly720Arg	missense_variant	Exon 16 of 16		NP_001393435.1
DSC2	NM_004949.5 link	c.*89G>A		3_prime_UTR_variant	Exon 17 of 17		NP_004940.1	Q02487-2
DSC2	NM_001406507.1 link	c.*89G>A		3_prime_UTR_variant	Exon 17 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DSC2	ENST00000280904.11 link	c.2587G>A	p.Gly863Arg	missense_variant	Exon 16 of 16	1	NM_024422.6	ENSP00000280904.6	Q02487-1
DSC2	ENST00000251081 link	c.*89G>A		3_prime_UTR_variant	Exon 17 of 17	1		ENSP00000251081.6	Q02487-2
DSC2	ENST00000648081.1 link	c.2158G>A	p.Gly720Arg	missense_variant	Exon 17 of 17			ENSP00000497441.1	A0A3B3ISU0
DSC2	ENST00000682357.1 link	c.2158G>A	p.Gly720Arg	missense_variant	Exon 16 of 16			ENSP00000507826.1	A0A3B3ISU0

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000275

AC:

AN:

251128

Hom.:

AF XY:

0.000332

AC XY:

AN XY:

135716

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000590

AC:

862

AN:

1461814

Hom.:

Cov.:

AF XY:

0.000608

AC XY:

442

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000661

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000683

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000223

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000454

Hom.:

Bravo

AF:

0.000306

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:3

Sep 05, 2017

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: The DSC2 c.2587G>A (p.Gly863Arg) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have not been confirmed by any in vitro/vivo functional studies. This variant was found in 34/122138 control chromosomes at a frequency of 0.0002784, which is approximately 28 times the estimated maximal expected allele frequency of a pathogenic DSC2 variant (0.00001), suggesting this variant is likely a benign polymorphism. This variant has been reported in affected individuals with DCM or ARVD. One ARVD patient also carried PKP2 variant c.917_918delCC, suggesting variant of interest may not be the primary cause of the phenotype. However, since ARVD is a known clinical entity that sometimes follows a digenic inheritance, we cannot exclude the pathogenicy of variant of interest based on the co-occurrence of PKP2 variant c.917_918delCC. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS-possibly benign unitl more information becomes available. -

Sep 23, 2016

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 06, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Gly863Arg var iant has been reported in the literature in one individual with DCM and 1 indivi dual with ARVC (Elliott 2010, Cox 2011). This variant has been identified in 0.0 3% (33/121305) of chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs147109895). Computational prediction tools and conservation analysis suggest that the p.Gly863Arg variant may impact the protei n, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of this variant is uncertain, its f requency suggests that it is more likely to be benign. -

not provided

Uncertain:3

Nov 01, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in multiple individuals with ARVC referred for genetic testing at GeneDx and in published literature; many of these individuals also harbored different pathogenic variants in other ARVC-related genes (PMID: 21606396, 21636032, 23671136, 28341588, 31402444, 33652588); Reported in a patient with DCM and in a patient with ventricular fibrillation (PMID: 25163546, 29032884); This variant is associated with the following publications: (PMID: 23671136, 28341588, 28471438, 23911551, 23299917, 21636032, 20716751, 37937776, 29032884, 31402444, 33652588, 25163546, 21606396) -

Aug 14, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2587G>A; p.Gly863Arg variant (rs147109895) was observed in both patient and control individuals assessed for dilated cardiomyopathy (Elliott, 2010). In addition the p.Gly863Arg variant was reported in one patient analyzed for arrhythmogenic right ventricular dysplasia/cardiomyopathy, whom also carried a frameshift PKP2 allele associated with this disease (Cox, 2011). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.06 percent in the South Asian population (identified on 19 out of 30,770 chromosomes), and is listed in the ClinVar database with uncertain significance (Variation ID: 46183). The glycine at position 863 is highly conserved and computational analyses of the p.Gly863Arg variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Gly863Arg variant with certainty. -

Mar 07, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Arrhythmogenic right ventricular dysplasia 11

Uncertain:2Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiomyopathy

Uncertain:1

Dec 13, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with arginine at codon 863 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy, in two individuals affected with arrhythmogenic cardiomyopathy, in an individual suspected to be affected with hypertrophic cardiomyopathy, and in an individual who experienced a idiopathic ventricular fibrillation event (PMID: 20716751, 28341588, 29032884, 30847666, 33652588). This variant has also been reported in another individual affected with arrhythmogenic right ventricular cardiomyopathy who also carried a pathogenic variant in the PKP2 gene (PMID: 21606396) and in an individual suspected to be affected with dilated cardiomyopathy who also carried a pathogenic variant in the SCN5A gene (PMID: 30847666). This variant has been identified in 74/282526 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant allele frequency is thought to be higher than expected for DSC2-related disorders, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Familial isolated arrhythmogenic right ventricular dysplasia

Uncertain:1

Sep 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype

Benign:1

Sep 23, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Pathogenic

0.82

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

D;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.20

T;T

MetaSVM

Uncertain

0.35

MutationAssessor

Pathogenic

3.5

H;.

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-5.5

D;.

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.63

MutPred

0.60

Loss of sheet (P = 0.0315);.;

MVP

0.93

MPC

0.47

ClinPred

0.60

GERP RS

5.9

Varity_R

0.62

gMVP

0.81

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