rs2006791

chr4-3485510-A-Gchr4-3485510-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173660.5(DOK7):c.533-29A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 1,549,968 control chromosomes in the GnomAD database, including 405,822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41746 hom., cov: 33)
  • Exomes 𝑓: 0.72 (364076 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.339

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-3485510-A-G is Benign according to our data. Variant chr4-3485510-A-G is described in ClinVar as [Benign]. Clinvar id is 262878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.533-29A>G		intron_variant		ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.533-29A>G		intron_variant		1	NM_173660.5	P1

Frequencies

GnomAD3 genomes AF: 0.738 AC: 112131 AN: 152014 Hom.: 41692 Cov.: 33

Gnomad AFR AF: 0.720

Gnomad AMI AF: 0.845

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.932

Gnomad SAS AF: 0.815

Gnomad FIN AF: 0.791

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.744

GnomAD3 exomes AF: 0.765 AC: 168870 AN: 220616 Hom.: 65378 AF XY: 0.761 AC XY: 91519 AN XY: 120248

Gnomad AFR exome AF: 0.728

Gnomad AMR exome AF: 0.858

Gnomad ASJ exome AF: 0.734

Gnomad EAS exome AF: 0.935

Gnomad SAS exome AF: 0.811

Gnomad FIN exome AF: 0.788

Gnomad NFE exome AF: 0.706

Gnomad OTH exome AF: 0.754

GnomAD4 exome AF: 0.719 AC: 1005208 AN: 1397836 Hom.: 364076 Cov.: 59 AF XY: 0.722 AC XY: 498361 AN XY: 690728

Gnomad4 AFR exome AF: 0.727

Gnomad4 AMR exome AF: 0.849

Gnomad4 ASJ exome AF: 0.730

Gnomad4 EAS exome AF: 0.942

Gnomad4 SAS exome AF: 0.813

Gnomad4 FIN exome AF: 0.784

Gnomad4 NFE exome AF: 0.696

Gnomad4 OTH exome AF: 0.729

GnomAD4 genome AF: 0.738 AC: 112241 AN: 152132 Hom.: 41746 Cov.: 33 AF XY: 0.746 AC XY: 55505 AN XY: 74372

Gnomad4 AFR AF: 0.720

Gnomad4 AMR AF: 0.808

Gnomad4 ASJ AF: 0.737

Gnomad4 EAS AF: 0.931

Gnomad4 SAS AF: 0.816

Gnomad4 FIN AF: 0.791

Gnomad4 NFE AF: 0.702

Gnomad4 OTH AF: 0.746

Alfa AF: 0.717 Hom.: 7249

Bravo AF: 0.738

Asia WGS AF: 0.861 AC: 2996 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Congenital myasthenic syndrome 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Fetal akinesia deformation sequence 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	11
Dann	Benign	0.71

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: rs2006791; hg19: chr4-3487237;