chr4-3493006-C-CGCCACTGGCAGCCACTCCT
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_173660.5(DOK7):c.1021_1039dup(p.Ser347CysfsTer28) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,410,594 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. I340I) has been classified as Benign.
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
DOK7
NM_173660.5 frameshift
NM_173660.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.87
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 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 44 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-3493006-C-CGCCACTGGCAGCCACTCCT is Pathogenic according to our data. Variant chr4-3493006-C-CGCCACTGGCAGCCACTCCT is described in ClinVar as [Pathogenic]. Clinvar id is 434960.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DOK7 | NM_173660.5 | c.1021_1039dup | p.Ser347CysfsTer28 | frameshift_variant | 7/7 | ENST00000340083.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DOK7 | ENST00000340083.6 | c.1021_1039dup | p.Ser347CysfsTer28 | frameshift_variant | 7/7 | 1 | NM_173660.5 | P1 | |
DOK7 | ENST00000515886.5 | c.91_109dup | p.Ser37CysfsTer28 | frameshift_variant | 4/4 | 2 | |||
DOK7 | ENST00000643608.1 | c.589_607dup | p.Ser203CysfsTer28 | frameshift_variant | 5/8 | ||||
DOK7 | ENST00000507039.5 | c.*242_*260dup | 3_prime_UTR_variant | 7/7 | 2 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
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34
GnomAD4 exome AF: 0.00000142 AC: 2AN: 1410594Hom.: 0 Cov.: 111 AF XY: 0.00 AC XY: 0AN XY: 698602
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111
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698602
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GnomAD4 genome Cov.: 34
GnomAD4 genome
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34
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Congenital myasthenic syndrome 10 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 10, 2015 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at