rs397517409

Positions:

chr18-31083026-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024422.6(DSC2):c.977A>C(p.Gln326Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,612,928 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.655

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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSC2	NM_024422.6 linkuse as main transcript	c.977A>C	p.Gln326Pro	missense_variant	8/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5 linkuse as main transcript	c.977A>C	p.Gln326Pro	missense_variant	8/17		NP_004940.1
DSC2	NM_001406506.1 linkuse as main transcript	c.548A>C	p.Gln183Pro	missense_variant	8/16		NP_001393435.1
DSC2	NM_001406507.1 linkuse as main transcript	c.548A>C	p.Gln183Pro	missense_variant	8/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11 linkuse as main transcript	c.977A>C	p.Gln326Pro	missense_variant	8/16	1	NM_024422.6	ENSP00000280904	P1	Q02487-1
DSC2	ENST00000251081.8 linkuse as main transcript	c.977A>C	p.Gln326Pro	missense_variant	8/17	1		ENSP00000251081		Q02487-2
DSC2	ENST00000648081.1 linkuse as main transcript	c.548A>C	p.Gln183Pro	missense_variant	9/17			ENSP00000497441
DSC2	ENST00000682357.1 linkuse as main transcript	c.548A>C	p.Gln183Pro	missense_variant	8/16			ENSP00000507826

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152246

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1460682

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726632

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 25, 2012

Variant classified as Uncertain Significance - Favor Pathogenic. The Gln326Pro v ariant in DSC2 has not been reported in the literature and was not detected in 8 ,600 European American and 4,400 African American chromosomes screened by the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). This variant h as been identified in 3 individuals (2 with ARVC, 1 with DCM) tested by our labo ratory. One individual (with ARVC) was homozygous (an affected family member was heterozygous) and another individual (with ARVC) carried another likely pathoge nic variant in the same gene. The individual with DCM carried a second, likely p athogenic variant in a DCM gene. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, absence from the ge neral population is consistent with pathogenicity; however, homozygosity in 1 in dividual and the presence of a second, likely pathogenic variant in another indi vidual raise some doubt as to whether this variant can cause disease. Additional studies are needed to fully assess its clinical significance. -

Arrhythmogenic right ventricular dysplasia 11

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 46205). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 326 of the DSC2 protein (p.Gln326Pro). This variant is present in population databases (rs397517409, gnomAD 0.007%). -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 28, 2023

This missense variant replaces glutamine with proline at codon 326 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 1/31398 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. -

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

Aug 15, 2023

This missense variant replaces glutamine with proline at codon 326 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/31398 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;.;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.59

D;D;D

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.1

M;M;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-4.2

D;D;.

REVEL

Benign

0.29

Sift

Uncertain

0.0090

D;D;.

Sift4G

Benign

0.070

T;T;.

Polyphen

0.40

B;B;.

Vest4

0.69

MVP

0.64

MPC

0.47

ClinPred

0.93

GERP RS

5.3

Varity_R

0.95

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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