NM_001943.5:c.3G>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 11P and 4B. PVS1PS1_ModeratePP5BS2

The NM_001943.5(DSG2):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000111 in 1,259,226 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).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000099 ( 0 hom. )

Consequence

DSG2
NM_001943.5 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 3.70

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 7 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 16 pathogenic variants. Next in-frame start position is after 534 CDS bases. Genomic position: 31522093. Lost 0.159 part of the original CDS.

PS1

Another start lost variant in NM_001943.5 (DSG2) was described as [Pathogenic] in Lovd

PP5

Variant 18-31498254-G-A is Pathogenic according to our data. Variant chr18-31498254-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 657863.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2, Likely_pathogenic=3}. Variant chr18-31498254-G-A is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG2	NM_001943.5 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 15	ENST00000261590.13	NP_001934.2	Q14126
DSG2	XM_047437315.1 link	c.-570G>A		5_prime_UTR_variant	Exon 1 of 16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DSG2	ENST00000261590.13 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 15	1	NM_001943.5	ENSP00000261590.8	Q14126
DSG2	ENST00000683654.1 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 7			ENSP00000506971.1	A0A804HIA2
DSG2	ENST00000682241.2 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 7			ENSP00000507600.2	A0A804HJQ3
DSG2	ENST00000585206.1 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 6	2		ENSP00000462503.1	J3KSI6

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151930

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:

0.00000993

AC:

AN:

1107296

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

526458

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:

0.0000118

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151930

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74226

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

May 14, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Reported in patients with ARVC in published literature but detailed clinical information was not included (PMID: 36264615); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20829228, 36264615) -

Aug 11, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DSG2: PS1:Moderate, PVS1:Moderate, PM2:Supporting, PS4:Supporting -

Arrhythmogenic right ventricular dysplasia 10

Pathogenic:2Uncertain:1

Nov 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the DSG2 mRNA. The next in-frame methionine is located at codon 179. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 17105751, 20829228). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 657863). 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). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jun 05, 2024

KardioGenetik, Herz- und Diabeteszentrum NRW

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_moderate, PS4_supporting, PM2_supporting -

Jul 12, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Oct 02, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant alters methionine at codon 1 of the DSG2 mRNA that serves as the translation initiation codon. An alternate in-frame methionine downstream of the initiator methionine occurs at codon 179 in extracellular cadherin domain 2, after signal peptide and propeptide. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two siblings affected with arrhythmogenic right ventricular cardiomyopathy, along with a second missense variant of uncertain significance in the same gene (PMID: 20829228), and in an individual with unspecified phenotype (PMID: 33968641). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, clinical relevance of loss-of-function DSG2 variants in autosomal dominant arrhythmogenic right ventricular cardiomyopathy is not yet clearly established. 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

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

T;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Benign

-0.55

PROVEAN

Benign

-1.4

N;.

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.92

P;.

Vest4

0.58

MutPred

0.99

Loss of glycosylation at P5 (P = 0.1075);Loss of glycosylation at P5 (P = 0.1075);

MVP

0.82

ClinPred

0.92

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.63

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