18-31074842-T-C

Position:

chr18-31074842-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_024422.6(DSC2):c.1729A>G(p.Ile577Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: 3.33

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 -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07567686).

BP6

Variant 18-31074842-T-C is Benign according to our data. Variant chr18-31074842-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46170.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5, Benign=1}. Variant chr18-31074842-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6 linkuse as main transcript	c.1729A>G	p.Ile577Val	missense_variant	12/16	ENST00000280904.11	NP_077740.1	Q02487-1
DSC2	NM_004949.5 linkuse as main transcript	c.1729A>G	p.Ile577Val	missense_variant	12/17		NP_004940.1	Q02487-2
DSC2	NM_001406506.1 linkuse as main transcript	c.1300A>G	p.Ile434Val	missense_variant	12/16		NP_001393435.1
DSC2	NM_001406507.1 linkuse as main transcript	c.1300A>G	p.Ile434Val	missense_variant	12/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DSC2	ENST00000280904.11 linkuse as main transcript	c.1729A>G	p.Ile577Val	missense_variant	12/16	1	NM_024422.6	ENSP00000280904.6	Q02487-1
DSC2	ENST00000251081.8 linkuse as main transcript	c.1729A>G	p.Ile577Val	missense_variant	12/17	1		ENSP00000251081.6	Q02487-2
DSC2	ENST00000648081.1 linkuse as main transcript	c.1300A>G	p.Ile434Val	missense_variant	13/17			ENSP00000497441.1	A0A3B3ISU0
DSC2	ENST00000682357.1 linkuse as main transcript	c.1300A>G	p.Ile434Val	missense_variant	12/16			ENSP00000507826.1	A0A3B3ISU0

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000267

AC:

AN:

251064

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135694

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:

0.0000462

Gnomad NFE exome

AF:

0.000573

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000328

AC:

480

AN:

1461756

Hom.:

Cov.:

AF XY:

0.000325

AC XY:

236

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

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:

0.000112

Gnomad4 NFE exome

AF:

0.000413

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000230

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000320

Hom.:

Bravo

AF:

0.000242

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000338

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2020	Reported in an individual with a personal and family history of DCM; this individual also harbored a frameshift variant in the TTN gene that was reported as likely pathogenic by the authors (Pugh et al., 2014); Reported as a non-segregating variant in a case of sporadic, pediatric DCM (Long et al., 2017); Reported in ClinVar as a variant of uncertain significance and as a likely benign variant; one clinical laboratory reports observing this variants in two adults with DCM, both of whom harbored another likely pathogenic variant (ClinVar Variant ID#46170; SCV000063095.5; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23861362, 24503780, 29367541, 31737537) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	DSC2: PM2:Supporting, BP4 -

Cardiomyopathy

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 13, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 08, 2017	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 03, 2014

The Ile577Val variant in DSC2 has been identified by our laboratory in 2 Caucasi an adults with DCM (including this family), both of whom carried another likely pathogenic variant. This variant has also been identified in 1/8600 European Ame rican chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washingto n.edu/EVS/; dbSNP rs201845641) and was reported in 1/186 controls in an unpublis hed study (ARVD/C Database, http://www.arvcdatabase.info). Computational predict ion tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, additional information is needed to fully assess the clinical significance of the Ile577Val variant. -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Feb 07, 2017

- -

Arrhythmogenic right ventricular dysplasia 11

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.091

T;.;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.73

T;T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.076

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.6

L;L;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.87

N;N;.

REVEL

Benign

0.10

Sift

Benign

0.082

T;T;.

Sift4G

Uncertain

0.035

D;D;.

Polyphen

0.014

B;B;.

Vest4

0.46

MVP

0.46

MPC

0.067

ClinPred

0.086

GERP RS

4.2

Varity_R

0.099

gMVP

0.62

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