rs1553847993
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM4_SupportingPP5
The NM_173660.5(DOK7):c.612_625delinsGGACGGTTCTA(p.Pro205_Pro209delinsAspGlySerThr) variant causes a protein altering change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S204S) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 34)
Consequence
DOK7
NM_173660.5 protein_altering
NM_173660.5 protein_altering
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.66
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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a domain IRS-type PTB (size 105) in uniprot entity DOK7_HUMAN there are 41 pathogenic changes around while only 1 benign (98%) in NM_173660.5
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_173660.5. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 4-3485618-CCCCACCAAGGGCC-GGACGGTTCTA is Pathogenic according to our data. Variant chr4-3485618-CCCCACCAAGGGCC-GGACGGTTCTA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434961.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DOK7 | NM_173660.5 | c.612_625delinsGGACGGTTCTA | p.Pro205_Pro209delinsAspGlySerThr | protein_altering_variant | 5/7 | ENST00000340083.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DOK7 | ENST00000340083.6 | c.612_625delinsGGACGGTTCTA | p.Pro205_Pro209delinsAspGlySerThr | protein_altering_variant | 5/7 | 1 | NM_173660.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
Cov.:
34
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 34
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Congenital myasthenic syndrome 10 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 10, 2015 | - - |
Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2022 | This variant, c.612_625delinsGGACGGTTCTA, is a complex sequence change that results in the deletion of 5 and insertion of 4 amino acid(s) in the DOK7 protein (p.Pro205_Pro209delinsAspGlySerThr). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with DOK7-related conditions. ClinVar contains an entry for this variant (Variation ID: 434961) Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at