rs59932476

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001164673.2(DOK7):c.742G>A(p.Gly248Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 1,572,772 control chromosomes in the GnomAD database, including 1,454 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.052 ( 291 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1163 hom. )

Consequence

DOK7
NM_001164673.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.31

Variant links:

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]

DOK7 links:

DOK7 (HGNC:):

DOK7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018548965).

BP6

Variant 4-3489777-G-A is Benign according to our data. Variant chr4-3489777-G-A is described in ClinVar as [Benign]. Clinvar id is 128914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3489777-G-A is described in Lovd as [Benign]. Variant chr4-3489777-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5 linkuse as main transcript	c.753G>A	p.Ala251Ala	synonymous_variant	6/7	ENST00000340083.6	NP_775931.3	Q18PE1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6 linkuse as main transcript	c.753G>A	p.Ala251Ala	synonymous_variant	6/7	1	NM_173660.5	ENSP00000344432.5		Q18PE1-1

Frequencies

GnomAD3 genomes

AF:

0.0521

AC:

7918

AN:

152002

Hom.:

289

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0922

Gnomad AMI

AF:

0.0771

Gnomad AMR

AF:

0.0679

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.0311

Gnomad SAS

AF:

0.0557

Gnomad FIN

AF:

0.0161

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0323

Gnomad OTH

AF:

0.0398

GnomAD3 exomes

AF:

0.0490

AC:

8993

AN:

183538

Hom.:

320

AF XY:

0.0471

AC XY:

4620

AN XY:

98148

show subpopulations

Gnomad AFR exome

AF:

0.0980

Gnomad AMR exome

AF:

0.100

Gnomad ASJ exome

AF:

0.0289

Gnomad EAS exome

AF:

0.0380

Gnomad SAS exome

AF:

0.0525

Gnomad FIN exome

AF:

0.0133

Gnomad NFE exome

AF:

0.0341

Gnomad OTH exome

AF:

0.0482

GnomAD4 exome

AF:

0.0361

AC:

51323

AN:

1420652

Hom.:

1163

Cov.:

AF XY:

0.0364

AC XY:

25577

AN XY:

702726

show subpopulations

Gnomad4 AFR exome

AF:

0.0912

Gnomad4 AMR exome

AF:

0.0940

Gnomad4 ASJ exome

AF:

0.0269

Gnomad4 EAS exome

AF:

0.0207

Gnomad4 SAS exome

AF:

0.0531

Gnomad4 FIN exome

AF:

0.0160

Gnomad4 NFE exome

AF:

0.0325

Gnomad4 OTH exome

AF:

0.0400

GnomAD4 genome

AF:

0.0521

AC:

7924

AN:

152120

Hom.:

291

Cov.:

AF XY:

0.0514

AC XY:

3821

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0921

Gnomad4 AMR

AF:

0.0684

Gnomad4 ASJ

AF:

0.0291

Gnomad4 EAS

AF:

0.0313

Gnomad4 SAS

AF:

0.0545

Gnomad4 FIN

AF:

0.0161

Gnomad4 NFE

AF:

0.0323

Gnomad4 OTH

AF:

0.0393

Alfa

AF:

0.0320

Hom.:

100

Bravo

AF:

0.0574

TwinsUK

AF:

0.0310

AC:

115

ALSPAC

AF:

0.0306

AC:

118

ESP6500AA

AF:

0.0877

AC:

382

ESP6500EA

AF:

0.0321

AC:

275

ExAC

AF:

0.0383

AC:

4520

Asia WGS

AF:

0.0580

AC:

201

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 11, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

0.60

DANN

Benign

0.57

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0055

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.49

PROVEAN

Benign

0.28

REVEL

Benign

0.20

Sift

Pathogenic

0.0

Vest4

0.21

MutPred

0.13

Gain of MoRF binding (P = 0.0066);

ClinPred

0.0034

GERP RS

-1.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over