rs142841727
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001943.5(DSG2):βc.2759T>Gβ(p.Val920Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00515 in 1,614,176 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (β β ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V920I) has been classified as Uncertain significance.
Frequency
Consequence
NM_001943.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.2759T>G | p.Val920Gly | missense_variant | 15/15 | ENST00000261590.13 | |
DSG2-AS1 | NR_045216.1 | n.1346-239A>C | intron_variant, non_coding_transcript_variant | ||||
DSG2 | XM_047437315.1 | c.2225T>G | p.Val742Gly | missense_variant | 16/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.2759T>G | p.Val920Gly | missense_variant | 15/15 | 1 | NM_001943.5 | P1 | |
DSG2-AS1 | ENST00000583706.5 | n.1384-239A>C | intron_variant, non_coding_transcript_variant | 5 | |||||
DSG2-AS1 | ENST00000657343.1 | n.697-239A>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00430 AC: 654AN: 152168Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.00368 AC: 918AN: 249158Hom.: 5 AF XY: 0.00365 AC XY: 493AN XY: 135176
GnomAD4 exome AF: 0.00524 AC: 7662AN: 1461890Hom.: 26 Cov.: 32 AF XY: 0.00503 AC XY: 3661AN XY: 727246
GnomAD4 genome ? AF: 0.00429 AC: 653AN: 152286Hom.: 4 Cov.: 32 AF XY: 0.00420 AC XY: 313AN XY: 74470
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:7
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 21, 2015 | p.Val920Gly in exon 15 of DSG2: This variant has been reported in several indivi duals with ARVC or DCM but did not segregate with disease in one family member ( Syrris 2007, Posch 2008, Barahona-Dussault 2010, Christensen 2010). It has been identified in 0.5% (316/66608) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142841727). This freq uency strongly argues against a disease causing role but is too low to establish this with confidence. - |
Benign, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Feb 23, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 04, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jun 24, 2015 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We consider this variant to be of uncertain significance, likely benign, given it is present in multiple control samples and that it failed to segregate with disease in one family. This variant has been reported in 6 unrelated cases with either ARVC or DCM and as many as 6 total cases. Syrris et al (2006) initially identified the variant in a 17 yo male who had a sudden cardiac arrest, a left ventricular variant of ARVC was confirmed on autopsy. The probandβs father who had a positive phenotype on MRI and an abnormal signal average ECG was found to be genotype positive for the variant. Posch et al (2008) identified the variant in two families with dilated cardiomyopathy (note they refer to the variant as p.Val919Gly due to a numbering difference). However they report that the variant did not segregate with the phenotype in one family. In that family five affected relatives had the variant but one affected relative did not, indicating that it is likely not the primary causative variant of their disease. Christensen et al (2010) also reported the variant in 1 case that was clinically borderline for ARVC. Quarta et al (2011) found p.Val920Gly in 2 out of 100 families with ARVC. This is a conservative amino acid change with a nonpolar Valine replaced by a nonpolar Glyceine. SIFT predicts the amino acid change to be tolerated while PolyPhen predicts it to be probably damaging to the resulting protein. A variant in a nearby codon (p.Pro925Ser) has been reported in association with disease (University Medical Center Groningen ARVD/C Genetic Variants Database). Syrris et al (2006) reported that the variant was absent in 200 presumably healthy controls. Posch et al (2008) identified p.Val920Gly in 2 out of 432 presumably healthy control individuals. Christensen et al (2010) reported that the variant was present in 3 out of 650 individuals from a control population. Cox et al (2011) reported that the variant was absent in 200 controls. The variant is listed in dbSNP (rs142841727) with frequency data from the ClinSeq project, where it was seen in 8 of 660 individuals. It is listed in 1000Genomes, but only in reference to the dbSNP entry (as of April 17th, 2013). Additionally the variant was found in 41/4135 Caucasians and 6/1948 African American individuals in the NHLBI Exome Sequencing Project dataset (as of April 17th, 2013). - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1Benign:2
Benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Jun 19, 2015 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 07, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | DSG2: BP4, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Cardiomyopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 03, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 08, 2018 | - - |
Arrhythmogenic right ventricular dysplasia 10 Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Arrhythmogenic right ventricular cardiomyopathy;C0878544:Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | May 02, 2018 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 08, 2017 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
DSG2-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 30, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at