rs797045528

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000340083.6(DOK7):​c.596del​(p.Ile199ThrfsTer47) 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 (β˜…β˜…). Synonymous variant affecting the same amino acid position (i.e. I199I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

DOK7
ENST00000340083.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.60
Variant links:
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
DOK7NM_173660.5 linkuse as main transcriptc.596del p.Ile199ThrfsTer47 frameshift_variant 5/7 ENST00000340083.6 NP_775931.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DOK7ENST00000340083.6 linkuse as main transcriptc.596del p.Ile199ThrfsTer47 frameshift_variant 5/71 NM_173660.5 ENSP00000344432 P1Q18PE1-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.0000122
AC:
3
AN:
245722
Hom.:
0
AF XY:
0.00000750
AC XY:
1
AN XY:
133372
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000270
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000344
AC:
5
AN:
1455508
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
723988
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000451
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
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 submitterclinical testingGenetic Services Laboratory, University of ChicagoJun 02, 2015- -
Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 25, 2023ClinVar 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 submitterclinical testingBaylor GeneticsMar 13, 2024- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJan 17, 2023Not 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs797045528; hg19: chr4-3487328; API