rs758537946

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_001943.5(DSG2):c.1072G>A(p.Ala358Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A358P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:6

Conservation

PhyloP100: 8.74

Variant links:

Genes affected

DSG2 (HGNC:3049): (desmoglein 2) This gene encodes a member of the desmoglein family and cadherin cell adhesion molecule superfamily of proteins. Desmogleins are calcium-binding transmembrane glycoprotein components of desmosomes, cell-cell junctions between epithelial, myocardial, and other cell types. The encoded preproprotein is proteolytically processed to generate the mature glycoprotein. This gene is present in a gene cluster with other desmoglein gene family members on chromosome 18. Mutations in this gene have been associated with arrhythmogenic right ventricular dysplasia, familial, 10. [provided by RefSeq, Jan 2016]

DSG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.768

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG2	NM_001943.5 linkuse as main transcript	c.1072G>A	p.Ala358Thr	missense_variant	9/15	ENST00000261590.13
DSG2	XM_047437315.1 linkuse as main transcript	c.538G>A	p.Ala180Thr	missense_variant	10/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG2	ENST00000261590.13 linkuse as main transcript	c.1072G>A	p.Ala358Thr	missense_variant	9/15	1	NM_001943.5	P1
DSG2	ENST00000683614.2 linkuse as main transcript	n.903G>A		non_coding_transcript_exon_variant	7/7

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249360

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135284

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727208

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 10, 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function. ClinVar contains an entry for this variant (Variation ID: 199805). This missense change has been observed in individual(s) with arrhythmogenic cardiomyopathy (PMID: 21636032, 25820315). This variant is present in population databases (rs758537946, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 358 of the DSG2 protein (p.Ala358Thr). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -

Primary dilated cardiomyopathy

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Blueprint Genetics

Sep 15, 2015

- -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 28, 2023

This missense variant replaces alanine with threonine at codon 358 of the DSG2 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 four unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 21636032, 25820315, 34998950). One of these individuals also carried a pathogenic variant in the PKP2 gene (PMID: 25820315). This variant has also been reported in an invividual affected with sudden unexplained death (PMID: 29016939). This variant has been identified in 2/249360 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. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 30, 2023

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2018

p.Ala358Thr (A358T) GCA>ACA: c.1072 G>A in exon 9 of the DSG2 gene (NM_001943.3). The Ala358Thr variant in the DSG2 gene has been reported with unclear significance in association with ARVC (Kapplinger J et al., 2011; Cox M et al., 2011). Kapplinger et al reported Ala358Thr in a patient with ARVC who harbored a large gene deletion in the PKP2 gene and another missense variant in the TMEM43 gene. Also, Cox et al. reported Ala358Thr as an unclassified variant when it was identified in their cohort of patient with ARVC. Ala358Thr results in a non-conservative amino acid substitution of a non-polar Alanine with a polar Threonine at a position that is conserved across species. In silico analysis predicts Ala358Thr is damaging to the protein structure/function. The Ala358Thr variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. With the information available at this time, we cannot definitively determine if Ala358Thr is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s). -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2022

The p.A358T variant (also known as c.1072G>A), located in coding exon 9 of the DSG2 gene, results from a G to A substitution at nucleotide position 1072. The alanine at codon 358 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts; however, clinical details were limited and additional alterations in other ARVC-related genes were identified (Cox MG et al. Circulation, 2011 Jun;123:2690-700; Groeneweg JA et al. Circ Cardiovasc Genet, 2015 Jun;8:437-46; Hellenthal N et al. Europace, 2017 Nov;19:1881-1890). This amino acid position is highly 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.0035

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

M_CAP

Benign

0.052

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.29

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.026

Polyphen

1.0

Vest4

0.60

MutPred

0.55

Gain of phosphorylation at A358 (P = 0.0786);

MVP

0.80

MPC

0.42

ClinPred

0.98

GERP RS

5.2

Varity_R

0.85

gMVP

0.68

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