rs539821357
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PVS1_ModeratePP5BS1_SupportingBS2
The NM_001943.5(DSG2):c.3039C>A(p.Tyr1013*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
DSG2
NM_001943.5 stop_gained
NM_001943.5 stop_gained
Scores
2
5
Clinical Significance
Conservation
PhyloP100: -2.01
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 Likely_benign. Variant got -2 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0947 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PP5
Variant 18-31546425-C-A is Pathogenic according to our data. Variant chr18-31546425-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 392196.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=5, Likely_pathogenic=1}.
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000116 (17/1461858) while in subpopulation EAS AF= 0.000403 (16/39700). AF 95% confidence interval is 0.000252. There are 0 homozygotes in gnomad4_exome. There are 9 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 17 AD gene.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DSG2 | ENST00000261590.13 | c.3039C>A | p.Tyr1013* | stop_gained | 15/15 | 1 | NM_001943.5 | ENSP00000261590.8 | ||
| DSG2-AS1 | ENST00000583706.5 | n.1384-519G>T | intron_variant | 5 | ||||||
| DSG2-AS1 | ENST00000657343.1 | n.697-519G>T | intron_variant |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000682 AC: 17AN: 249368Hom.: 0 AF XY: 0.0000739 AC XY: 10AN XY: 135280
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GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461858Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727230
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GnomAD4 genome 0.0000131 AC: 2AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74464
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 10 Pathogenic:1Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Tyr1013*) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 106 amino acid(s) of the DSG2 protein. This variant is present in population databases (rs539821357, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 392196). This variant disrupts a region of the DSG2 protein in which other variant(s) (p.Glu1020Alafs*18) have been determined to be pathogenic (PMID: 20864495, 21397041, 23381804). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Arrhythmogenic right ventricular dysplasia 10 (MIM#610193) and Dialted cardiomyopathy 1BB (MIM#612877). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. This gene is usually reported in association with autosomal dominant inheritance with reduced penetrance, however austosomal recessive inheritance has also been observed in more severe cases (OMIM). (I) 0112 - Variants in this gene are known to have reduced penetrance (OMIM). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of arrhythmogenic right ventricular dysplasia 10 (MIM#610193) and dialted cardiomyopathy 1BB (MIM#612877). (SB) 0601 - Variant is located in the well-established functional domain, desmoglein repeat 5 (Uniprot). It was shown that Dsg unique region (DUR, which contains desmoglein repeat 5) is required for protein stabilization as well as promoting stronger intercellular adhesion (PMID: 23128240). The tyrosine at position 1013 is one of the phosphorylation sites important for the formation of desmosomes and cell adhesion (PMID: 23911551). (SP) 0702 - A few truncation variants downstream to the one identified in this case have strong previous evidence for pathogenicity. These variants have been reported only in patients with Arrhythmogenic right ventricular dysplasia 10 (MIM#610193) but not Dilated cardiomyopathy (MIN#612877) (ClinVar, PMID: 23812740, 21397041, 26296472). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. The variant has been previously reported in patients with arrhythmogenic right ventricular dysplasia (ARVD) (ClinVar). It has also been reported as VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Cardiomyopathy Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 22, 2023 | This variant changes 1 nucleotide in exon 15 of the DSG2 gene, creating a premature translation stop signal in the last coding exon. This variant is expected to escape nonsense-mediated decay and be expressed as a truncated protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 34500006). This variant has been identified in 18/280770 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 30, 2016 | - - |
Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 15, 2024 | - - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 21, 2024 | Nonsense variant predicted to result in protein truncation as the last 106 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 31931689, 31983221, 34500006, 36129056, 35288587) - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 27, 2023 | The p.Y1013* variant (also known as c.3039C>A), located in coding exon 15 of the DSG2 gene, results from a C to A substitution at nucleotide position 3039. This changes the amino acid from a tyrosine to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of theDSG2 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 9% of the protein. The exact functional effect of this alteration is unknown. Additionally, based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
Vest4
GERP RS
Splicing
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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