18-31519866-C-T

Position:

chr18-31519866-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PM1PM2PM5PP3_StrongBS2

The NM_001943.5(DSG2):c.145C>T(p.Arg49Cys) 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 1,461,872 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R49H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:4

Conservation

PhyloP100: 0.610

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_pathogenic. Variant got 6 ACMG points.

PM1

In a propeptide (size 25) in uniprot entity DSG2_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_001943.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-31519867-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5 link	c.145C>T	p.Arg49Cys	missense_variant	3/15	ENST00000261590.13	NP_001934.2	Q14126
DSG2	XM_047437315.1 link	c.-390C>T		5_prime_UTR_variant	4/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13 link	c.145C>T	p.Arg49Cys	missense_variant	3/15	1	NM_001943.5	ENSP00000261590.8		Q14126

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249476

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135354

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727236

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:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2023	Reported in one individual from a cohort of individuals with HCM, DCM, and ARVC from the United Kingdom, though no patient-specific details were provided (Walsh et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31402444, 27532257, 16773573) -

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 arginine with cysteine at codon 49 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257). This variant has been identified in 2/249476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg49His, is known to cause arrhythmogenic right ventricular cardiomyopathy (Clinvar variation ID 16810), indicating that arginine at this position is important for DSG2 protein function. 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

Feb 12, 2021

Arrhythmogenic right ventricular dysplasia 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2022

This variant is present in population databases (rs762526848, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 49 of the DSG2 protein (p.Arg49Cys). This missense change has been observed in individual(s) with clinical features of DSG2-related conditions (PMID: 27532257). 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. This variant disrupts the p.Arg49 amino acid residue in DSG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19151369, 19863551, 20400443). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 450040). -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2024

The p.R49C variant (also known as c.145C>T), located in coding exon 3 of the DSG2 gene, results from a C to T substitution at nucleotide position 145. The arginine at codon 49 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in a large study of pathogenicity of Mendelian variants in cardiomyopathy patients, but clinical details are limited (Walsh R et al. Genet Med, 2017 Feb;19:192-203). Another variant at the same codon, p.R49H (c.146G>A), has been described in association with arrhythmogenic right ventricular cardiomyopathy (ARVC). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Uncertain

0.77

D;D

Eigen

Uncertain

0.39

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.92

D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Pathogenic

3.9

H;.

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-7.5

D;.

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.79

MutPred

0.88

Loss of MoRF binding (P = 0.0045);Loss of MoRF binding (P = 0.0045);

MVP

0.92

MPC

0.49

ClinPred

1.0

GERP RS

2.3

Varity_R

0.53

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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