chr18-31546667-G-A

Position:

chr18-31546667-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP4_StrongBS2

The NM_001943.5(DSG2):c.3281G>A(p.Gly1094Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.248

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:

DSG2-AS1 (HGNC:51311): (DSG2 antisense RNA 1)

DSG2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054800063).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSG2	NM_001943.5 linkuse as main transcript	c.3281G>A	p.Gly1094Asp	missense_variant	15/15	ENST00000261590.13	NP_001934.2
DSG2-AS1	NR_045216.1 linkuse as main transcript	n.1346-761C>T		intron_variant, non_coding_transcript_variant
DSG2	XM_047437315.1 linkuse as main transcript	c.2747G>A	p.Gly916Asp	missense_variant	16/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DSG2	ENST00000261590.13 linkuse as main transcript	c.3281G>A	p.Gly1094Asp	missense_variant	15/15	1	NM_001943.5	ENSP00000261590	P1
DSG2-AS1	ENST00000583706.5 linkuse as main transcript	n.1384-761C>T		intron_variant, non_coding_transcript_variant		5
DSG2-AS1	ENST00000657343.1 linkuse as main transcript	n.697-761C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249220

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135180

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:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000496

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 16, 2022

This missense variant replaces glycine with aspartic acid at codon 1094 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 not been reported in individuals affected with DSG2-related disorders in the literature. This variant has been identified in 1/249220 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. -

Arrhythmogenic right ventricular dysplasia 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 04, 2023

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: 580912). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1094 of the DSG2 protein (p.Gly1094Asp). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.24

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.61

M_CAP

Benign

0.012

MetaRNN

Benign

0.055

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.51

REVEL

Benign

0.093

Sift

Benign

0.22

Sift4G

Benign

0.15

Polyphen

0.013

Vest4

0.095

MutPred

0.099

Loss of glycosylation at S1093 (P = 0.0395);

MVP

0.51

MPC

0.11

ClinPred

0.070

GERP RS

2.4

Varity_R

0.025

gMVP

0.44

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