chr4-3492937-AC-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_173660.5(DOK7):βc.957delβ(p.Lys320SerfsTer136) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,398 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. P318P) has been classified as Likely benign.
Frequency
Consequence
NM_173660.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DOK7 | NM_173660.5 | c.957del | p.Lys320SerfsTer136 | frameshift_variant | 7/7 | ENST00000340083.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DOK7 | ENST00000340083.6 | c.957del | p.Lys320SerfsTer136 | frameshift_variant | 7/7 | 1 | NM_173660.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome AF: 7.18e-7 AC: 1AN: 1392398Hom.: 0 Cov.: 110 AF XY: 0.00000145 AC XY: 1AN XY: 687356
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Congenital myasthenic syndrome 10 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1992 | - - |
Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 01, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the DOK7 protein. Other variants that disrupt this region (p.Cys412*, p.Gln460*, p.Gly479Hisfs*13) have been observed in individuals with DOK7-related conditions (PMID: 20458068, 20012313, 28716243). This suggests that this may be a clinically significant region of the protein. This variant has been observed in individual(s) with congenital myasthenic syndrome (PMID: 22884442, 28024842). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 198626). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Lys320Serfs*136) in the DOK7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 185 amino acid(s) of the DOK7 protein. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 22, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at