chr2-219421474-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_001927.4(DES):c.1158C>T(p.Arg386Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
DES
NM_001927.4 synonymous
NM_001927.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.31
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 2-219421474-C-T is Benign according to our data. Variant chr2-219421474-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285963.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.1158C>T | p.Arg386Arg | synonymous_variant | 6/9 | 1 | NM_001927.4 | ENSP00000363071.3 | ||
DES | ENST00000477226.6 | n.632C>T | non_coding_transcript_exon_variant | 5/8 | 4 | |||||
DES | ENST00000492726.1 | n.553C>T | non_coding_transcript_exon_variant | 5/6 | 4 | |||||
DES | ENST00000683013.1 | n.546C>T | non_coding_transcript_exon_variant | 4/7 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152076Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251428Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135912
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GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461888Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15AN XY: 727246
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152194Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6AN XY: 74384
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 15, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | DES: BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 09, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 26, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 15, 2019 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 18, 2023 | The c.1158C>T variant (also known as p.R386R), located in coding exon 6 of the DES gene, results from a C to T substitution at nucleotide position 1158. This nucleotide substitution does not change the arginine at codon 386. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Desmin-related myofibrillar myopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
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Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at