rs41272699
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001927.4(DES):c.638C>T(p.Ala213Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,614,216 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. A213T) has been classified as Uncertain significance.
Frequency
Consequence
NM_001927.4 missense, splice_region
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 |
---|---|---|---|---|---|---|---|
DES | NM_001927.4 | c.638C>T | p.Ala213Val | missense_variant, splice_region_variant | 2/9 | ENST00000373960.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.638C>T | p.Ala213Val | missense_variant, splice_region_variant | 2/9 | 1 | NM_001927.4 | P1 | |
DES | ENST00000477226.6 | n.112C>T | splice_region_variant, non_coding_transcript_exon_variant | 1/8 | 4 | ||||
DES | ENST00000492726.1 | n.33C>T | splice_region_variant, non_coding_transcript_exon_variant | 1/6 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.00989 AC: 1505AN: 152228Hom.: 12 Cov.: 32
GnomAD3 exomes AF: 0.00921 AC: 2315AN: 251474Hom.: 24 AF XY: 0.00996 AC XY: 1354AN XY: 135908
GnomAD4 exome AF: 0.0146 AC: 21307AN: 1461870Hom.: 221 Cov.: 36 AF XY: 0.0142 AC XY: 10361AN XY: 727236
GnomAD4 genome ? AF: 0.00989 AC: 1506AN: 152346Hom.: 12 Cov.: 32 AF XY: 0.00890 AC XY: 663AN XY: 74492
ClinVar
Submissions by phenotype
not specified Benign:9
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 10, 2012 | Ala213Val in exon 2 of DES: This variant has been reported by several studies an d was initially thought to be disease causing (Goldfarb 2004, Bar 2004, Kostarev a 2006). However, it has been identified in 0.4% (8/2000) of chromosomes from a broad, though clinically and racially unspecified population (dbSNP rs41272699) and in 1.5% (102/7020) of European American chromosomes and 0.4% (14/3738) of Af rican American chromosomes by the NHBLI Exome sequencing project in a clinical c ohort that included individuals with heart disease (http://evs.gs.washington.edu /EVS). With a frequency this high the variant is considered to be benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 01, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 04, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
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 | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 03, 2018 | Variant summary: DES c.638C>T (p.Ala213Val) results in a non-conservative amino acid change located in the Intermediate filament, rod domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0094 in 278984 control chromosomes in the gnomAD database, including 28 homozygotes. The observed variant frequency is approximately 375 fold of the estimated maximal expected allele frequency for a pathogenic variant in DES causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.638C>T has been reported in the literature in individuals affected with Cardiomyopathy as well as in controls. In one study, the variant failed to segregate with disease in a family, being found in 4 healthy individuals and was absent in 1 affected individual (Taylor_2007). In functional studies, cells expressing the variant showed normal complete filamentous network (Bar_2005, Goudeau_2006). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:5Other:1
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 26, 2023 | - - |
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | This variant is associated with the following publications: (PMID: 33232181, 32105824, 22215463, 25736269, 17325244, 23861362, 20474083, 27618136, 22260945, 16865695, 21842594, 25617006, 23168288) - |
Desmin-related myofibrillar myopathy Benign:3
Benign, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | European (non-Finnish) population allele frequency is 1.5% (rs41272699, 1,953/129,178 alleles, 20 homozygotes in gnomAD v2.1). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria met: BA1 - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Myofibrillar myopathy Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Wellcome Centre for Mitochondrial Research, Newcastle University | Aug 16, 2016 | - - |
Congenital diaphragmatic hernia Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Mar 03, 2015 | It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family. - |
Myofibrillar Myopathy, Dominant Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Dilated cardiomyopathy 1I Benign:1
Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Neurogenic scapuloperoneal syndrome, Kaeser type Benign:1
Likely benign, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 15, 2023 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 15, 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at