rs779508279
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The NM_173660.5(DOK7):βc.1340_1354delβ(p.Leu447_Arg451del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000368 in 1,603,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.000066 ( 0 hom., cov: 34)
Exomes π: 0.000034 ( 0 hom. )
Consequence
DOK7
NM_173660.5 inframe_deletion
NM_173660.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.44
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
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Nonframeshift variant in NON repetitive region in NM_173660.5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DOK7 | NM_173660.5 | c.1340_1354del | p.Leu447_Arg451del | inframe_deletion | 7/7 | ENST00000340083.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DOK7 | ENST00000340083.6 | c.1340_1354del | p.Leu447_Arg451del | inframe_deletion | 7/7 | 1 | NM_173660.5 | P1 | |
DOK7 | ENST00000515886.5 | c.410_424del | p.Leu137_Arg141del | inframe_deletion | 4/4 | 2 | |||
DOK7 | ENST00000643608.1 | c.908_922del | p.Leu303_Arg307del | inframe_deletion | 5/8 | ||||
DOK7 | ENST00000507039.5 | c.*561_*575del | 3_prime_UTR_variant | 7/7 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152196Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000364 AC: 8AN: 219718Hom.: 0 AF XY: 0.0000576 AC XY: 7AN XY: 121546
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GnomAD4 exome AF: 0.0000338 AC: 49AN: 1451738Hom.: 0 AF XY: 0.0000347 AC XY: 25AN XY: 721222
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GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152196Hom.: 0 Cov.: 34 AF XY: 0.0000807 AC XY: 6AN XY: 74354
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The DOK7 p.Leu137_Arg141del variant was not identified in the literature but was identified in dbSNP (ID: rs779508279) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 10 of 251084 chromosomes at a frequency of 0.00003983 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 4 of 29126 chromosomes (freq: 0.000137), European (non-Finnish) in 5 of 109750 chromosomes (freq: 0.000046) and Latino in 1 of 33670 chromosomes (freq: 0.00003), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. This variant is an in-frame deletion resulting in the removal of codons 137 to 141; the impact of this alteration on DOK7 protein function is not known. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 26, 2019 | - - |
Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 27, 2022 | This variant, c.1340_1354del, results in the deletion of 5 amino acid(s) of the DOK7 protein (p.Leu447_Arg451del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs779508279, gnomAD 0.01%). 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: 465675). 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
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at