chr18-31535365-A-G
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001943.5(DSG2):c.1376A>G(p.Tyr459Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,612,140 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y459Y) has been classified as Likely benign.
Frequency
Consequence
NM_001943.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.1376A>G | p.Tyr459Cys | missense_variant | 10/15 | ENST00000261590.13 | |
DSG2 | XM_047437315.1 | c.842A>G | p.Tyr281Cys | missense_variant | 11/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.1376A>G | p.Tyr459Cys | missense_variant | 10/15 | 1 | NM_001943.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000328 AC: 50AN: 152252Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.00112 AC: 279AN: 248034Hom.: 8 AF XY: 0.00148 AC XY: 199AN XY: 134600
GnomAD4 exome AF: 0.000550 AC: 803AN: 1459770Hom.: 18 Cov.: 29 AF XY: 0.000823 AC XY: 598AN XY: 726250
GnomAD4 genome AF: 0.000328 AC: 50AN: 152370Hom.: 2 Cov.: 32 AF XY: 0.000523 AC XY: 39AN XY: 74508
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 10 Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Jun 08, 2024 | Downgraded variant due to updated local frequency - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Uncertain significance, flagged submission | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 21, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | - - |
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 01, 2016 | Variant summary: DSG2 c.1376A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 4/4 in-silico tools predict a damaging outcome for this variant, however, functional studies have not been carried out to confirm these predictions. This variant is found in 139/111860 control chromosomes (5 homozygotes) at a frequency of 0.0012426. The variant is predominantly found in South Asians (132/15646; 0.0084367). These frequencies are 124-843 times the maximal expected frequency of a pathogenic DSG2 allele (0.00001), highly suggesting this variant is benign. Additionally, the variant has been reported in 1 HCM patient to co-occur with a pathogenic variant, TNNT2 R92W. Although one research center reports this variant as likely pathogenic, they provide no evidence to independently evaluate. Taken together, this is probably a normal variant given the high frequency in controls and at least one reported co-occurrence with a pathogenic TNNT2 allele, thus this DSG2 variant was classified as likely benign. - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2017 | 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, Academic Medical Center | - | - - |
Cardiomyopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 12, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 05, 2018 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 07, 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at