rs606231129
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_173660.5(DOK7):βc.1263delβ(p.Ser422HisfsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,611,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.000039 ( 0 hom., cov: 34)
Exomes π: 0.000012 ( 0 hom. )
Consequence
DOK7
NM_173660.5 frameshift
NM_173660.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0800
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 14 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 9 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-3493242-GC-G is Pathogenic according to our data. Variant chr4-3493242-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3493242-GC-G is described in Lovd as [Pathogenic]. Variant chr4-3493242-GC-G is described in Lovd as [Pathogenic]. Variant chr4-3493242-GC-G is described in Lovd as [Pathogenic]. Variant chr4-3493242-GC-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DOK7 | NM_173660.5 | c.1263del | p.Ser422HisfsTer34 | frameshift_variant | 7/7 | ENST00000340083.6 | NP_775931.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DOK7 | ENST00000340083.6 | c.1263del | p.Ser422HisfsTer34 | frameshift_variant | 7/7 | 1 | NM_173660.5 | ENSP00000344432 | P1 | |
DOK7 | ENST00000643608.1 | c.831del | p.Ser278HisfsTer34 | frameshift_variant | 5/8 | ENSP00000495701 | ||||
DOK7 | ENST00000515886.5 | c.333del | p.Ser112HisfsTer34 | frameshift_variant | 4/4 | 2 | ENSP00000492194 | |||
DOK7 | ENST00000507039.5 | c.*484del | 3_prime_UTR_variant | 7/7 | 2 | ENSP00000423614 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152192Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000126 AC: 3AN: 237478Hom.: 0 AF XY: 0.00000767 AC XY: 1AN XY: 130418
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1459632Hom.: 0 Cov.: 95 AF XY: 0.0000124 AC XY: 9AN XY: 726086
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152192Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3AN XY: 74354
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital myasthenic syndrome 10 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 31618753). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000242521 / PMID: 18626973). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Nov 08, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 22, 2023 | Frameshift variant predicted to result in protein truncation, as the last 83 amino acids are replaced with 33 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18626973, 23219351, 22661499, 31618753) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 17, 2020 | - - |
Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 27, 2023 | This sequence change creates a premature translational stop signal (p.Ser422Hisfs*34) in the DOK7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 83 amino acid(s) of the DOK7 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with clinical features of congenital myasthenic syndrome and/or developmental delay and exercise intolerance (PMID: 18626973, 23219351, 25326637, 31618753). ClinVar contains an entry for this variant (Variation ID: 242521). This variant disrupts the C-terminus of the DOK7 protein. Other variant(s) that disrupt this region (p.Gly479Hisfs*13, p.Gln460*) have been observed in individuals with DOK7-related conditions (PMID: 20012313, 20458068). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. - |
Fetal akinesia deformation sequence 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 10, 2024 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at