rs797045528
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_173660.5(DOK7):c.596delT(p.Ile199fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000344 in 1,455,508 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
DOK7
NM_173660.5 frameshift
NM_173660.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.60
Genes affected
DOK7 (HGNC:26594): (docking protein 7) The protein encoded by this gene is essential for neuromuscular synaptogenesis. The protein functions in aneural activation of muscle-specific receptor kinase, which is required for postsynaptic differentiation, and in the subsequent clustering of the acetylcholine receptor in myotubes. This protein can also induce autophosphorylation of muscle-specific receptor kinase. Mutations in this gene are a cause of familial limb-girdle myasthenia autosomal recessive, which is also known as congenital myasthenic syndrome type 1B. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]
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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 4-3485601-AT-A is Pathogenic according to our data. Variant chr4-3485601-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 210856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3485601-AT-A is described in Lovd as [Pathogenic]. Variant chr4-3485601-AT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DOK7 | NM_173660.5 | c.596delT | p.Ile199fs | frameshift_variant | 5/7 | ENST00000340083.6 | NP_775931.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DOK7 | ENST00000340083.6 | c.596delT | p.Ile199fs | frameshift_variant | 5/7 | 1 | NM_173660.5 | ENSP00000344432.5 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
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34
GnomAD3 exomes AF: 0.0000122 AC: 3AN: 245722Hom.: 0 AF XY: 0.00000750 AC XY: 1AN XY: 133372
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GnomAD4 exome AF: 0.00000344 AC: 5AN: 1455508Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 723988
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GnomAD4 genome Cov.: 34
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34
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital myasthenic syndrome 10 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 02, 2015 | - - |
Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 25, 2023 | ClinVar contains an entry for this variant (Variation ID: 210856). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DOK7 protein in which other variant(s) (p.Asp433Argfs*18) have been determined to be pathogenic (PMID: 17439981, 22661499; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Studies have shown that this premature translational stop signal alters DOK7 gene expression (PMID: 18626973). This premature translational stop signal has been observed in individual(s) with congenital myasthenic syndrome (PMID: 18626973). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs797045528, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Ile199Thrfs*47) in the DOK7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 306 amino acid(s) of the DOK7 protein. - |
Fetal akinesia deformation sequence 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 13, 2024 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 306 amino acids are replaced with 46 different amino acids, and other loss-of-function variants have been reported downstream in HGMD.; This variant is associated with the following publications: (PMID: 18626973) - |
Computational scores
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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