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.Glu1020fs) 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
NM_001943.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.71
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]
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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=5}. 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 | UniProt |
---|---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.3059_3062delAGAG | p.Glu1020fs | frameshift_variant | 15/15 | ENST00000261590.13 | NP_001934.2 | |
DSG2 | XM_047437315.1 | c.2525_2528delAGAG | p.Glu842fs | frameshift_variant | 16/16 | XP_047293271.1 | ||
DSG2-AS1 | NR_045216.1 | n.1346-538_1346-535delCTCT | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.3059_3062delAGAG | p.Glu1020fs | frameshift_variant | 15/15 | 1 | NM_001943.5 | ENSP00000261590.8 | ||
DSG2-AS1 | ENST00000583706.5 | n.1384-538_1384-535delCTCT | intron_variant | 5 | ||||||
DSG2-AS1 | ENST00000657343.1 | n.697-538_697-535delCTCT | intron_variant |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152168Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000361 AC: 9AN: 249404Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135304
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GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461866Hom.: 0 AF XY: 0.0000358 AC XY: 26AN XY: 727234
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74348
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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
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.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. - |
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. - |
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 | Mendelics | May 04, 2022 | - - |
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 | Sep 17, 2024 | 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
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
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