4-3492937-ACCC-ACC

Position:

• chr4-3492937-ACCC-ACC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_173660.5(DOK7):​c.957del​(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 (★★). Synonymous variant affecting the same amino acid position (i.e. P318P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DOK7 NM_173660.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.60

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 48 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-3492937-AC-A is Pathogenic according to our data. Variant chr4-3492937-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 198626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3492937-AC-A is described in Lovd as [Pathogenic].

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: 1 AN: 1392398 Hom.: 0 Cov.: 110 AF XY: 0.00000145 AC XY: 1 AN XY: 687356

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: 9.25e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs794727884; hg19: chr4-3494664;