rs147109895
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_ModerateBP6BS1
The NM_024422.6(DSC2):c.2587G>A(p.Gly863Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000555 in 1,614,050 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G863E) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00059 ( 1 hom. )
Consequence
DSC2
NM_024422.6 missense
NM_024422.6 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 6.72
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 Likely_benign. Variant got -5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19868788).
BP6
Variant 18-31068134-C-T is Benign according to our data. Variant chr18-31068134-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46183.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}. Variant chr18-31068134-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00059 (862/1461814) while in subpopulation NFE AF= 0.000683 (760/1111984). AF 95% confidence interval is 0.000643. There are 1 homozygotes in gnomad4_exome. There are 442 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| DSC2 | NM_024422.6 | c.2587G>A | p.Gly863Arg | missense_variant | 16/16 | ENST00000280904.11 | |
| DSC2 | NM_001406506.1 | c.2158G>A | p.Gly720Arg | missense_variant | 16/16 | ||
| DSC2 | NM_001406507.1 | c.*89G>A | 3_prime_UTR_variant | 17/17 | |||
| DSC2 | NM_004949.5 | c.*89G>A | 3_prime_UTR_variant | 17/17 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| DSC2 | ENST00000280904.11 | c.2587G>A | p.Gly863Arg | missense_variant | 16/16 | 1 | NM_024422.6 | P1 | |
| DSC2 | ENST00000251081.8 | c.*89G>A | 3_prime_UTR_variant | 17/17 | 1 | ||||
| DSC2 | ENST00000648081.1 | c.2158G>A | p.Gly720Arg | missense_variant | 17/17 | ||||
| DSC2 | ENST00000682357.1 | c.2158G>A | p.Gly720Arg | missense_variant | 16/16 |
Frequencies
GnomAD3 genomes 0.000224 AC: 34AN: 152118Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000275 AC: 69AN: 251128Hom.: 0 AF XY: 0.000332 AC XY: 45AN XY: 135716
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GnomAD4 exome AF: 0.000590 AC: 862AN: 1461814Hom.: 1 Cov.: 31 AF XY: 0.000608 AC XY: 442AN XY: 727198
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GnomAD4 genome 0.000223 AC: 34AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74438
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 06, 2016 | Variant classified as Uncertain Significance - Favor Benign. The p.Gly863Arg var iant has been reported in the literature in one individual with DCM and 1 indivi dual with ARVC (Elliott 2010, Cox 2011). This variant has been identified in 0.0 3% (33/121305) of chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs147109895). Computational prediction tools and conservation analysis suggest that the p.Gly863Arg variant may impact the protei n, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of this variant is uncertain, its f requency suggests that it is more likely to be benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 05, 2017 | Variant summary: The DSC2 c.2587G>A (p.Gly863Arg) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have not been confirmed by any in vitro/vivo functional studies. This variant was found in 34/122138 control chromosomes at a frequency of 0.0002784, which is approximately 28 times the estimated maximal expected allele frequency of a pathogenic DSC2 variant (0.00001), suggesting this variant is likely a benign polymorphism. This variant has been reported in affected individuals with DCM or ARVD. One ARVD patient also carried PKP2 variant c.917_918delCC, suggesting variant of interest may not be the primary cause of the phenotype. However, since ARVD is a known clinical entity that sometimes follows a digenic inheritance, we cannot exclude the pathogenicy of variant of interest based on the co-occurrence of PKP2 variant c.917_918delCC. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS-possibly benign unitl more information becomes available. - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Sep 23, 2016 | - - |
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 17, 2023 | Identified in multiple individuals with ARVC referred for genetic testing at GeneDx and in published literature (Cox et al., 2011; Kapplinger et al., 2011; Bhonsale et al. 2013; Proost et al., 2017; Ye et al., 2019; Vallverdu-Prats et al., 2021); many of these individuals also harbored different pathogenic variants in other ARVC-related genes; Reported in a patient with DCM and in a patient with ventricular fibrillation (Haas et al., 2015; Leinonen et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23671136, 28341588, 28471438, 23911551, 23299917, 21636032, 20716751, 29032884, 31402444, 25163546, 33652588, 21606396) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 14, 2017 | The c.2587G>A; p.Gly863Arg variant (rs147109895) was observed in both patient and control individuals assessed for dilated cardiomyopathy (Elliott, 2010). In addition the p.Gly863Arg variant was reported in one patient analyzed for arrhythmogenic right ventricular dysplasia/cardiomyopathy, whom also carried a frameshift PKP2 allele associated with this disease (Cox, 2011). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.06 percent in the South Asian population (identified on 19 out of 30,770 chromosomes), and is listed in the ClinVar database with uncertain significance (Variation ID: 46183). The glycine at position 863 is highly conserved and computational analyses of the p.Gly863Arg variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Gly863Arg variant with certainty. - |
| Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Mar 07, 2017 | - - |
Arrhythmogenic right ventricular dysplasia 11 Uncertain:2Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | - - |
| Uncertain significance, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Jul 30, 2015 | - - |
| 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 13, 2023 | This missense variant replaces glycine with arginine at codon 863 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy, in two individuals affected with arrhythmogenic cardiomyopathy, in an individual suspected to be affected with hypertrophic cardiomyopathy, and in an individual who experienced a idiopathic ventricular fibrillation event (PMID: 20716751, 28341588, 29032884, 30847666, 33652588). This variant has also been reported in another individual affected with arrhythmogenic right ventricular cardiomyopathy who also carried a pathogenic variant in the PKP2 gene (PMID: 21606396) and in an individual suspected to be affected with dilated cardiomyopathy who also carried a pathogenic variant in the SCN5A gene (PMID: 30847666). This variant has been identified in 74/282526 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant allele frequency is thought to be higher than expected for DSC2-related disorders, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces glycine with arginine at codon 863 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy, in two individuals affected with arrhythmogenic cardiomyopathy, in an individual suspected to be affected with hypertrophic cardiomyopathy, and in an individual who experienced a idiopathic ventricular fibrillation event (PMID: 20716751, 28341588, 29032884, 30847666, 33652588). This variant has also been reported in another individual affected with arrhythmogenic right ventricular cardiomyopathy who also carried a pathogenic variant in the PKP2 gene (PMID: 21606396) and in an individual suspected to be affected with dilated cardiomyopathy who also carried a pathogenic variant in the SCN5A gene (PMID: 30847666). This variant has been identified in 74/282526 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant allele frequency is thought to be higher than expected for DSC2-related disorders, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 23, 2021 | This alteration is classified as likely 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Uncertain
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;.
Polyphen
D;.
Vest4
MutPred
Loss of sheet (P = 0.0315);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at