rs75882680
Positions:
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_001927.4(DES):āc.669T>Cā(p.Ile223=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,614,180 control chromosomes in the GnomAD database, including 315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.027 ( 171 hom., cov: 32)
Exomes š: 0.0032 ( 144 hom. )
Consequence
DES
NM_001927.4 synonymous
NM_001927.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.155
Genes affected
DES (HGNC:2770): (desmin) This gene encodes a muscle-specific class III intermediate filament. Homopolymers of this protein form a stable intracytoplasmic filamentous network connecting myofibrils to each other and to the plasma membrane. Mutations in this gene are associated with desmin-related myopathy, a familial cardiac and skeletal myopathy (CSM), and with distal myopathies. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.51).
BP6
?
Variant 2-219420280-T-C is Benign according to our data. Variant chr2-219420280-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 36001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219420280-T-C is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=0.155 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0878 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DES | NM_001927.4 | c.669T>C | p.Ile223= | synonymous_variant | 3/9 | ENST00000373960.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.669T>C | p.Ile223= | synonymous_variant | 3/9 | 1 | NM_001927.4 | P1 | |
DES | ENST00000477226.6 | n.143T>C | non_coding_transcript_exon_variant | 2/8 | 4 | ||||
DES | ENST00000492726.1 | n.64T>C | non_coding_transcript_exon_variant | 2/6 | 4 | ||||
DES | ENST00000683013.1 | n.57T>C | non_coding_transcript_exon_variant | 1/7 |
Frequencies
GnomAD3 genomes ? AF: 0.0265 AC: 4030AN: 152170Hom.: 171 Cov.: 32
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GnomAD3 exomes AF: 0.00745 AC: 1873AN: 251462Hom.: 74 AF XY: 0.00561 AC XY: 763AN XY: 135904
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GnomAD4 exome AF: 0.00321 AC: 4694AN: 1461892Hom.: 144 Cov.: 35 AF XY: 0.00275 AC XY: 2000AN XY: 727246
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GnomAD4 genome ? AF: 0.0265 AC: 4036AN: 152288Hom.: 171 Cov.: 32 AF XY: 0.0254 AC XY: 1894AN XY: 74474
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:18
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:7
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 15, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
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 | Eurofins Ntd Llc (ga) | Mar 12, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 19, 2011 | Ile223Ile in exon 3 of DES: This variant is classified as benign because it does not change the amino acid and is frequent in the general population (rs7588268, MAF >1%). - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 09, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Desmin-related myofibrillar myopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Cardiomyopathy Benign:2
Benign, criteria provided, single submitter | curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 15, 2015 | - - |
Dilated cardiomyopathy 1I Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Myofibrillar Myopathy, Dominant Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Neurogenic scapuloperoneal syndrome, Kaeser type Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 07, 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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