rs59932476

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_173660.5(DOK7):c.753G>A(p.Ala251Ala) variant causes a synonymous 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. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A251A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.052 ( 291 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1163 hom. )

Consequence

DOK7
NM_173660.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.31

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 10
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
fetal akinesia deformation sequence 3
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
fetal akinesia deformation sequence 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DOK7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 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 VariationId is 128914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.32 with no splicing effect.

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 rank	MANE	Protein	UniProt
DOK7	NM_173660.5 link	c.753G>A	p.Ala251Ala	synonymous_variant	Exon 6 of 7	ENST00000340083.6	NP_775931.3	Q18PE1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6 link	c.753G>A	p.Ala251Ala	synonymous_variant	Exon 6 of 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

GnomAD2 exomes

AF:

0.0490

AC:

8993

AN:

183538

AF XY:

0.0471

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 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

African (AFR)

AF:

0.0912

AC:

2983

AN:

32712

American (AMR)

AF:

0.0940

AC:

3686

AN:

39206

Ashkenazi Jewish (ASJ)

AF:

0.0269

AC:

681

AN:

25352

East Asian (EAS)

AF:

0.0207

AC:

776

AN:

37534

South Asian (SAS)

AF:

0.0531

AC:

4297

AN:

80884

European-Finnish (FIN)

AF:

0.0160

AC:

794

AN:

49540

Middle Eastern (MID)

AF:

0.0553

AC:

316

AN:

5718

European-Non Finnish (NFE)

AF:

0.0325

AC:

35438

AN:

1090902

Other (OTH)

AF:

0.0400

AC:

2352

AN:

58804

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

3169

6338

9507

12676

15845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1444

2888

4332

5776

7220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0521

AC:

7924

AN:

152120

Hom.:

291

Cov.:

AF XY:

0.0514

AC XY:

3821

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0921

AC:

3818

AN:

41476

American (AMR)

AF:

0.0684

AC:

1047

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0291

AC:

101

AN:

3472

East Asian (EAS)

AF:

0.0313

AC:

162

AN:

5172

South Asian (SAS)

AF:

0.0545

AC:

263

AN:

4826

European-Finnish (FIN)

AF:

0.0161

AC:

171

AN:

10616

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0323

AC:

2196

AN:

67950

Other (OTH)

AF:

0.0393

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

379

758

1137

1516

1895

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0368

Hom.:

341

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

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 11, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 08, 2016

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 provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

0.60

(source)

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

PhyloP100

-2.3

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

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over