rs727502987
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM4_SupportingBS2
The NM_001943.5(DSG2):βc.1038_1040delβ(p.Lys346del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000052 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.000026 ( 0 hom., cov: 32)
Exomes π: 0.000055 ( 0 hom. )
Consequence
DSG2
NM_001943.5 inframe_deletion
NM_001943.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.39
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 -3 ACMG points.
PM4
?
Nonframeshift variant in NON repetitive region in NM_001943.5. Strenght limited to Supporting due to length of the change: 1aa.
BS2
?
High AC in GnomAdExome4 at 80 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.1038_1040del | p.Lys346del | inframe_deletion | 9/15 | ENST00000261590.13 | |
DSG2 | XM_047437315.1 | c.504_506del | p.Lys168del | inframe_deletion | 10/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.1038_1040del | p.Lys346del | inframe_deletion | 9/15 | 1 | NM_001943.5 | P1 | |
DSG2 | ENST00000683614.2 | n.869_871del | non_coding_transcript_exon_variant | 7/7 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152186Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249096Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135156
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GnomAD4 exome AF: 0.0000547 AC: 80AN: 1461678Hom.: 0 AF XY: 0.0000523 AC XY: 38AN XY: 727130
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 19, 2014 | The Lys346del variant in DSG2 has been reported in 2 individuals with ARVC and w as absent from 1400 control chromosomes (Tan 2010, Quarta 2011). In addition, th is variant has been identified by our laboratory in 1 individual with HCM (LMM u npublished data). Two of these individuals (Tan 2010, LMM) carried other likely pathogenic variants, including 1 in the DSG2 gene on the other allele (in trans) . This variant is a deletion of 1 amino acid at position 346 and is not predicte d to alter the protein reading-frame, though it is unclear if this deletion will impact the protein. In summary, the clinical significance of the Lys346del vari ant is uncertain. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 07, 2023 | This variant results in a deletion of single amino acid at codon 346 position of the DSG2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606390, 27532257, 29759408). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy in trans with a pathogenic DSG2 c.523+2T>C variant, which could explain the observed phenotype (PMID: 20857253, 29759408). This variant has been identified in 2/249096 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Feb 02, 2017 | - - |
Arrhythmogenic right ventricular dysplasia 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2023 | This variant, c.1038_1040del, results in the deletion of 1 amino acid(s) of the DSG2 protein (p.Lys346del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs727502987, gnomAD 0.002%). This variant has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20857253, 21606390, 27532257). ClinVar contains an entry for this variant (Variation ID: 163205). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of one amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 23810894, 20857253, 23871885, 23671136, 24563469, 27532257, 31402444, 31386562, 33190517, 21606390, 29759408, 32114801, 24585727) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 28, 2021 | The c.1038_1040delGAA variant (also known as p.K346del) is located in coding exon 9 of the DSG2 gene. This variant results from an in-frame GAA deletion at nucleotide positions 1038 to 1040. This results in the in-frame deletion of a lysine at codon 346. This variant has been identified in individuals with arrhythmogenic right ventricular cardiomyopathy, some of whom had additional cardiac variants detected (Tan BY et al. J Cardiovasc Transl Res, 2010 Dec;3:663-73; Quarta G et al. Circulation, 2011 Jun;123:2701-9; Bhonsale A et al. Circ Arrhythm Electrophysiol, 2013 Jun;6:569-78; Orgeron GM et al. J Am Heart Assoc, 2017 Jun;6). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on available evidence to date, the clinical significance of this alteration remains unclear. - |
Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 03, 2022 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at