rs2344208

chr4-3473380-G-Achr4-3473380-G-C

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.101-26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,607,292 control chromosomes in the GnomAD database, including 16,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2497 hom., cov: 34)
  • Exomes 𝑓: 0.14 (14471 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.10

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=-0.93).
• BP6: Variant 4-3473380-G-A is Benign according to our data. Variant chr4-3473380-G-A is described in ClinVar as [Benign]. Clinvar id is 262864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3473380-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.101-26G>A		intron_variant		ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.101-26G>A		intron_variant		1	NM_173660.5	P1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25453 AN: 152094 Hom.: 2495 Cov.: 34

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0501

Gnomad SAS AF: 0.0635

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.184

GnomAD3 exomes AF: 0.127 AC: 30058 AN: 237486 Hom.: 2314 AF XY: 0.126 AC XY: 16426 AN XY: 130668

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.0920

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.0500

Gnomad SAS exome AF: 0.0728

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.136 AC: 197318 AN: 1455080 Hom.: 14471 Cov.: 33 AF XY: 0.134 AC XY: 96940 AN XY: 723876

Gnomad4 AFR exome AF: 0.265

Gnomad4 AMR exome AF: 0.0981

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.0327

Gnomad4 SAS exome AF: 0.0714

Gnomad4 FIN exome AF: 0.105

Gnomad4 NFE exome AF: 0.142

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.167 AC: 25476 AN: 152212 Hom.: 2497 Cov.: 34 AF XY: 0.163 AC XY: 12138 AN XY: 74414

Gnomad4 AFR AF: 0.261

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.0500

Gnomad4 SAS AF: 0.0640

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.183

Alfa AF: 0.100 Hom.: 173

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 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	-0.93
Cadd	Benign	0.20
Dann	Benign	0.74

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: rs2344208; hg19: chr4-3475107;