chr18-31546440-AAGAG-A

Position:

chr18-31546440-AAGAG-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PVS1_ModeratePP5BS2

The ENST00000261590.13(DSG2):c.3059_3062del(p.Glu1020AlafsTer18) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000254 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1019R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

DSG2
ENST00000261590.13 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:3

Conservation

PhyloP100: 5.71

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 -1 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.09 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PP5

Variant 18-31546440-AAGAG-A is Pathogenic according to our data. Variant chr18-31546440-AAGAG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199827.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Pathogenic=4, Uncertain_significance=3}. Variant chr18-31546440-AAGAG-A is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSG2	NM_001943.5 linkuse as main transcript	c.3059_3062del	p.Glu1020AlafsTer18	frameshift_variant	15/15	ENST00000261590.13	NP_001934.2
DSG2-AS1	NR_045216.1 linkuse as main transcript	n.1346-538_1346-535del		intron_variant, non_coding_transcript_variant
DSG2	XM_047437315.1 linkuse as main transcript	c.2525_2528del	p.Glu842AlafsTer18	frameshift_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.3059_3062del	p.Glu1020AlafsTer18	frameshift_variant	15/15	1	NM_001943.5	ENSP00000261590	P1
DSG2-AS1	ENST00000583706.5 linkuse as main transcript	n.1384-538_1384-535del		intron_variant, non_coding_transcript_variant		5
DSG2-AS1	ENST00000657343.1 linkuse as main transcript	n.697-538_697-535del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152168

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000361

AC:

AN:

249404

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135304

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:

0.0000928

Gnomad NFE exome

AF:

0.0000619

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461866

Hom.:

AF XY:

0.0000358

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000749

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74348

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:

0.000188

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Glu1020Alafs*18) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 99 amino acid(s) of the DSG2 protein. This variant is present in population databases (rs746854378, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495, 21397041, 23381804). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 199827). This variant disrupts a region of the DSG2 protein in which other variant(s) (p.Glu1083Ser) have been observed in individuals with DSG2-related conditions (PMID: 21636032). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 31, 2019	The c.3059_3062delAGAG (p.Glu1020Alafs18) variant in the DSG2 gene is predicted to introduce a premature translational termination codon, expecting to disrupt the last 99 amino acids of the DSG2 protein. This variant has been reported in individuals and a family affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495, 21397041, 23381804). This variant is present in population databases at low frequency (gnomAD 0.003609%). Therefore, this c.3059_3062delAGAG (p.Glu1020Alafs18) variant in the DSG2 gene is classified as likely pathogenic. -

Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Sep 12, 2024	ACMG criteria used: PVS1_Moderate, PS4, PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 20, 2024	This variant deletes 4 nucleotides in exon 15 of the DSG2 gene, creating a frameshift in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, functional studies have not been reported for this variant. This variant has been identified in eight unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 21397041, 20864495, 23381804, 33821670, 34263121, 36431211) and has been reported to segregate with disease in one of the families (PMID: 21397041). This variant has also been observed in individuals affected with conduction defect (PMID: 21397041), hypertrophic cardiomyopathy (PMID: 34500006), or dilated cardiomyopathy (PMID: 36129056), and in unaffected family members (PMID 21397041) as well as in individuals without history of cardiovascular events (PMID: 33968641, 34135346). Furthermore, the variant has been reported in compound heterozygous state with another DSG2 variant in three individual affected with arrhythmogenic cardiomyopathy (PMID: 37418234). This variant has been identified in 9/249404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, 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

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 15, 2023	This variant deletes 4 nucleotides in exon 15 of the DSG2 gene, creating a frameshift in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, functional studies have not been reported for this variant. This variant has been identified in eight unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 21397041, 20864495, 23381804, 33821670, 34263121, 36431211) and has been reported to segregate with disease in one of the families (PMID: 21397041). This variant has also been observed in individuals affected with conduction defect (PMID: 21397041), hypertrophic cardiomyopathy (PMID: 34500006), or dilated cardiomyopathy (PMID: 36129056), and in unaffected family members (PMID 21397041) as well as in individuals without history of cardiovascular events (PMID: 33968641, 34135346). Furthermore, the variant has been reported in compound heterozygous state with another DSG2 variant in three individual affected with arrhythmogenic cardiomyopathy (PMID: 37418234). This variant has been identified in 9/249404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Nov 28, 2018	- -

Primary dilated cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Apr 10, 2015

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2022

The c.3059_3062delAGAG variant, located in coding exon 15 of the DSG2 gene, results from a deletion of 4 nucleotides between nucleotide positions 3059 and 3062, causing a translational frameshift with a predicted alternate stop codon (p.E1020Afs*18). This alteration occurs at the 3' terminus of theDSG2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 99 amino acids (8.9%) of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant has been described in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) or features consistent with ARVC and an individual described as having left-dominant arrhythmogenic cardiomyopathy (Christensen AH et al. J Med Genet. 2010;47(11):736-44; Lahtinen AM et al. Heart Rhythm. 2011;8(8):1214-21; Rasmussen TB et al. Hum Mutat. 2013;34(5):697-705; van Lint FHM et al. Circ Genom Precis Med. 2019 08;12(8):e002467; Lao N et al. Eur Heart J Case Rep. 2021 Jun;5(6)). This variant was observed to co-segregate with ARVC in three siblings in one family; however, two relatives with this variant exhibited either absent or limited phenotype, suggesting reduced penetrance (Lahtinen AM et al. Heart Rhythm. 2011;8(8):1214-21). This variant has also been detected in cohorts without known ARVC; however, clinical details were limited (Abicht A et al. Cardiovasc Diagn Ther. 2021 Apr;11(2):637-649; Lacaze P et al. NPJ Genom Med. 2021 Jun;6(1):51). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Dilated cardiomyopathy 1BB

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Oct 08, 2015

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Nov 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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