rs786205429
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBS1BS2
The NM_024422.6(DSC2):c.2687_2688insGA(p.Ala897LysfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.0106 in 1,613,982 control chromosomes in the GnomAD database, including 114 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0087 ( 11 hom., cov: 32)
Exomes 𝑓: 0.011 ( 103 hom. )
Consequence
DSC2
NM_024422.6 frameshift
NM_024422.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.14
Genes affected
DSC2 (HGNC:3036): (desmocollin 2) This gene encodes a member of the desmocollin protein subfamily. Desmocollins, along with desmogleins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmocollin family members on chromosome 18. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia-11, and reduced protein expression has been described in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
PM4
?
Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 903 codons.
BP6
?
Variant 18-31068033-T-TTC is Benign according to our data. Variant chr18-31068033-T-TTC is described in ClinVar as [Likely_benign]. Clinvar id is 46186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00872 (1327/152258) while in subpopulation NFE AF= 0.0146 (991/68012). AF 95% confidence interval is 0.0138. There are 11 homozygotes in gnomad4. There are 633 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd at 11 SD gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.2687_2688insGA | p.Ala897LysfsTer4 | frameshift_variant | 16/16 | ENST00000280904.11 | |
DSC2 | NM_001406506.1 | c.2258_2259insGA | p.Ala754LysfsTer4 | frameshift_variant | 16/16 | ||
DSC2 | NM_001406507.1 | c.*189_*190insGA | 3_prime_UTR_variant | 17/17 | |||
DSC2 | NM_004949.5 | c.*189_*190insGA | 3_prime_UTR_variant | 17/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.2687_2688insGA | p.Ala897LysfsTer4 | frameshift_variant | 16/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.*189_*190insGA | 3_prime_UTR_variant | 17/17 | 1 | ||||
DSC2 | ENST00000648081.1 | c.2258_2259insGA | p.Ala754LysfsTer4 | frameshift_variant | 17/17 | ||||
DSC2 | ENST00000682357.1 | c.2258_2259insGA | p.Ala754LysfsTer4 | frameshift_variant | 16/16 |
Frequencies
GnomAD3 genomes ? AF: 0.00872 AC: 1327AN: 152140Hom.: 11 Cov.: 32
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GnomAD3 exomes AF: 0.00843 AC: 2119AN: 251230Hom.: 10 AF XY: 0.00854 AC XY: 1159AN XY: 135792
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GnomAD4 exome AF: 0.0108 AC: 15742AN: 1461724Hom.: 103 Cov.: 31 AF XY: 0.0106 AC XY: 7673AN XY: 727154
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:21
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1Benign:5
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 31, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Uncertain significance, no assertion criteria provided | literature only | OMIM | Jul 01, 2010 | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Dec 09, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Benign:6
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
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 | Jan 14, 2013 | Ala897fs in exon 16 of DSC2: This variant is not expected to have clinical signi ficance because it has been identified in 1.3% (111/8254) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS/). This variant leads to a frameshift starting at pos ition 897 and a subsequent truncation that removes the terminal amino acid of th e DSC2 protein. Although it was initially reported in 3 Caucasian individuals wi th ARVC probands while absent from 400 ethnically matched control alleles, it ha s subsequently been detected in several control cohorts at frequencies that argu e against a disease causing role (0.8%-1.5%, see http://arvcdatabase.info). The overall frequency of this variant strongly argues against a primary disease-caus ing role, although we cannot rule out that it may modify disease severity when p resent with other disease-causing variants. - |
Benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Eurofins Ntd Llc (ga) | May 31, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 26, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | DSC2: BS1, BS2 - |
Cardiomyopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 09, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 24, 2017 | - - |
Arrhythmogenic right ventricular cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Jul 01, 2015 | - - |
Primary familial hypertrophic cardiomyopathy Benign:1
Benign, no assertion criteria provided | clinical testing | Blueprint Genetics | Nov 08, 2013 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 15, 2013 | No disease association in appropriately sized case-control study(ies) - |
Familial isolated arrhythmogenic right ventricular dysplasia Benign:1
Benign, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Jul 07, 2023 | - - |
Computational scores
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Name
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at