rs397516706

Variant summary

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

The NM_001943.5(DSG2):​c.3059_3062delAGAG​(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).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

DSG2
NM_001943.5 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U: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-AS1 (HGNC:51311): (DSG2 antisense RNA 1)

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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 0.0888 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: {Uncertain_significance=3, Pathogenic=4, Likely_pathogenic=6}. 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 rank MANE Protein UniProt
DSG2NM_001943.5 linkc.3059_3062delAGAG p.Glu1020AlafsTer18 frameshift_variant Exon 15 of 15 ENST00000261590.13 NP_001934.2 Q14126
DSG2XM_047437315.1 linkc.2525_2528delAGAG p.Glu842AlafsTer18 frameshift_variant Exon 16 of 16 XP_047293271.1
DSG2-AS1NR_045216.1 linkn.1346-538_1346-535delCTCT intron_variant Intron 3 of 5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DSG2ENST00000261590.13 linkc.3059_3062delAGAG p.Glu1020AlafsTer18 frameshift_variant Exon 15 of 15 1 NM_001943.5 ENSP00000261590.8 Q14126
DSG2-AS1ENST00000583706.5 linkn.1384-538_1384-535delCTCT intron_variant Intron 3 of 5 5
DSG2-AS1ENST00000657343.1 linkn.697-538_697-535delCTCT intron_variant Intron 3 of 3

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152168
Hom.:
0
Cov.:
32
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:
9
AN:
249404
Hom.:
0
AF XY:
0.0000443
AC XY:
6
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:
36
AN:
1461866
Hom.:
0
AF XY:
0.0000358
AC XY:
26
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:
5
AN:
152168
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
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:10Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10 Pathogenic:4
Jul 25, 2019
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 31, 2019
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3059_3062delAGAG (p.Glu1020Alafs*18) 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.Glu1020Alafs*18) variant in the DSG2 gene is classified as likely pathogenic. -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

May 04, 2022
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1Uncertain:1
Jul 20, 2024
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Sep 12, 2024
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG criteria used: PVS1_Moderate, PS4, PM2 -

Cardiomyopathy Pathogenic:1Uncertain:1
Aug 15, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Nov 28, 2018
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Pathogenic:1
Apr 10, 2015
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB Pathogenic:1
Apr 12, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1
Sep 17, 2024
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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); external communication). 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 and individuals 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; external communication). Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, it may represent a risk factor or a milder allele with incomplete penetrance that manifests clinically only in the presence of additional genetic or environmental factors. -

Dilated cardiomyopathy 1BB Pathogenic:1
Oct 08, 2015
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

not provided Uncertain:1
Nov 02, 2021
AiLife Diagnostics, AiLife Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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.

Other links and lift over

dbSNP: rs397516706; hg19: chr18-29126403; API