rs2006802

Variant names:

• chr4-3485708-G-A
• rs2006802
• NM_173660.5:c.652+50G>A

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.652+50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,475,030 control chromosomes in the GnomAD database, including 1,773 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (969 hom., cov: 34)
  • Exomes 𝑓: 0.0084 (804 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.589

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=-0.83).
• BP6: Variant 4-3485708-G-A is Benign according to our data. Variant chr4-3485708-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5	c.652+50G>A		intron_variant	Intron 5 of 6	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.652+50G>A		intron_variant	Intron 5 of 6	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes AF: 0.0645 AC: 9812 AN: 152182 Hom.: 965 Cov.: 34

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0315

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00340

Gnomad OTH AF: 0.0550

GnomAD3 exomes AF: 0.0171 AC: 2261 AN: 132148 Hom.: 180 AF XY: 0.0137 AC XY: 1002 AN XY: 72964

Gnomad AFR exome AF: 0.212

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.00469

Gnomad SAS exome AF: 0.00618

Gnomad FIN exome AF: 0.0000674

Gnomad NFE exome AF: 0.00327

Gnomad OTH exome AF: 0.0170

GnomAD4 exome AF: 0.00838 AC: 11080 AN: 1322730 Hom.: 804 Cov.: 33 AF XY: 0.00774 AC XY: 5012 AN XY: 647248

Gnomad4 AFR exome AF: 0.218

Gnomad4 AMR exome AF: 0.0171

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.00273

Gnomad4 SAS exome AF: 0.00513

Gnomad4 FIN exome AF: 0.000108

Gnomad4 NFE exome AF: 0.00251

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0646 AC: 9835 AN: 152300 Hom.: 969 Cov.: 34 AF XY: 0.0624 AC XY: 4650 AN XY: 74474

Gnomad4 AFR AF: 0.215

Gnomad4 AMR AF: 0.0314

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00340

Gnomad4 OTH AF: 0.0549

Alfa AF: 0.0298 Hom.: 65

Bravo AF: 0.0724

Asia WGS AF: 0.0230 AC: 82 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.60

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: rs2006802; hg19: chr4-3487435;