rs886043080
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001927.4(DES):c.1213del(p.Tyr405ThrfsTer42) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y405Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Consequence
DES
NM_001927.4 frameshift
NM_001927.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.91
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-219421528-CT-C is Pathogenic according to our data. Variant chr2-219421528-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 285337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219421528-CT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DES | NM_001927.4 | c.1213del | p.Tyr405ThrfsTer42 | frameshift_variant | 6/9 | ENST00000373960.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.1213del | p.Tyr405ThrfsTer42 | frameshift_variant | 6/9 | 1 | NM_001927.4 | P1 | |
DES | ENST00000477226.6 | n.687del | non_coding_transcript_exon_variant | 5/8 | 4 | ||||
DES | ENST00000492726.1 | n.608del | non_coding_transcript_exon_variant | 5/6 | 4 | ||||
DES | ENST00000683013.1 | n.601del | non_coding_transcript_exon_variant | 4/7 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Desmin-related myofibrillar myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 04, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 285337). This variant has not been reported in the literature in individuals affected with DES-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr405Thrfs*42) in the DES gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DES are known to be pathogenic (PMID: 23575897). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 22, 2015 | - - |
Computational scores
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Calibrated prediction
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Prediction
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