18-31545870-T-C
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_001943.5(DSG2):āc.2484T>Cā(p.Asp828=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 1,614,108 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0020 ( 2 hom., cov: 32)
Exomes š: 0.00019 ( 2 hom. )
Consequence
DSG2
NM_001943.5 synonymous
NM_001943.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.426
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 Benign. Variant got -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.66).
BP6
Variant 18-31545870-T-C is Benign according to our data. Variant chr18-31545870-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178020.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=6}. Variant chr18-31545870-T-C is described in Lovd as [Benign]. Variant chr18-31545870-T-C is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.426 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00197 (300/152236) while in subpopulation AFR AF= 0.00701 (291/41534). AF 95% confidence interval is 0.00634. There are 2 homozygotes in gnomad4. There are 131 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 300 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.2484T>C | p.Asp828= | synonymous_variant | 15/15 | ENST00000261590.13 | |
DSG2-AS1 | NR_045216.1 | n.1382A>G | non_coding_transcript_exon_variant | 4/6 | |||
DSG2 | XM_047437315.1 | c.1950T>C | p.Asp650= | synonymous_variant | 16/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.2484T>C | p.Asp828= | synonymous_variant | 15/15 | 1 | NM_001943.5 | P1 | |
DSG2-AS1 | ENST00000583706.5 | n.1420A>G | non_coding_transcript_exon_variant | 4/6 | 5 | ||||
DSG2-AS1 | ENST00000657343.1 | n.733A>G | non_coding_transcript_exon_variant | 4/4 |
Frequencies
GnomAD3 genomes AF: 0.00197 AC: 299AN: 152118Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.000477 AC: 119AN: 249308Hom.: 0 AF XY: 0.000318 AC XY: 43AN XY: 135250
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GnomAD4 exome AF: 0.000189 AC: 277AN: 1461872Hom.: 2 Cov.: 31 AF XY: 0.000154 AC XY: 112AN XY: 727236
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GnomAD4 genome AF: 0.00197 AC: 300AN: 152236Hom.: 2 Cov.: 32 AF XY: 0.00176 AC XY: 131AN XY: 74426
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:11
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Arrhythmogenic right ventricular dysplasia 10 Uncertain:1Benign:1
Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2012 | p.Asp828Asp in Exon 15 of DSG2: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence and has been identified in 0.6% (18/2984) of Afr ican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS;). - |
Cardiomyopathy Benign:2
Likely benign, no assertion criteria provided | clinical testing | Cohesion Phenomics | Sep 23, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 08, 2018 | - - |
Arrhythmogenic right ventricular cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 03, 2015 | 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
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at