4-3493229-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_173660.5(DOK7):c.1243C>T(p.Pro415Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0414 in 1,611,910 control chromosomes in the GnomAD database, including 1,980 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P415R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.062 ( 461 hom., cov: 34)

Exomes 𝑓: 0.039 ( 1519 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.413

Publications

17 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017016828).

BP6

Variant 4-3493229-C-T is Benign according to our data. Variant chr4-3493229-C-T is described in ClinVar as Benign. ClinVar VariationId is 128908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5 link	c.1243C>T	p.Pro415Ser	missense_variant	Exon 7 of 7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DOK7	ENST00000340083.6 link	c.1243C>T	p.Pro415Ser	missense_variant	Exon 7 of 7	1	NM_173660.5	ENSP00000344432.5
DOK7	ENST00000643608.1 link	c.811C>T	p.Pro271Ser	missense_variant	Exon 5 of 8			ENSP00000495701.1
DOK7	ENST00000515886.5 link	c.313C>T	p.Pro105Ser	missense_variant	Exon 4 of 4	2		ENSP00000492194.1
DOK7	ENST00000507039.5 link	c.*464C>T		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000423614.1

Frequencies

GnomAD3 genomes

AF:

0.0622

AC:

9464

AN:

152194

Hom.:

452

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.0715

Gnomad ASJ

AF:

0.0317

Gnomad EAS

AF:

0.0393

Gnomad SAS

AF:

0.0621

Gnomad FIN

AF:

0.0165

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0341

Gnomad OTH

AF:

0.0454

GnomAD2 exomes

AF:

0.0533

AC:

12757

AN:

239344

AF XY:

0.0506

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.107

Gnomad ASJ exome

AF:

0.0328

Gnomad EAS exome

AF:

0.0417

Gnomad FIN exome

AF:

0.0136

Gnomad NFE exome

AF:

0.0358

Gnomad OTH exome

AF:

0.0537

GnomAD4 exome

AF:

0.0393

AC:

57303

AN:

1459598

Hom.:

1519

Cov.:

AF XY:

0.0396

AC XY:

28742

AN XY:

726088

show subpopulations

African (AFR)

AF:

0.113

AC:

3793

AN:

33456

American (AMR)

AF:

0.102

AC:

4564

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.0300

AC:

782

AN:

26108

East Asian (EAS)

AF:

0.0256

AC:

1015

AN:

39668

South Asian (SAS)

AF:

0.0616

AC:

5307

AN:

86150

European-Finnish (FIN)

AF:

0.0166

AC:

863

AN:

51878

Middle Eastern (MID)

AF:

0.0725

AC:

418

AN:

5768

European-Non Finnish (NFE)

AF:

0.0340

AC:

37815

AN:

1111644

Other (OTH)

AF:

0.0455

AC:

2746

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

4140

8280

12419

16559

20699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1554

3108

4662

6216

7770

<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:

0.0623

AC:

9495

AN:

152312

Hom.:

461

Cov.:

AF XY:

0.0612

AC XY:

4557

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.122

AC:

5090

AN:

41554

American (AMR)

AF:

0.0720

AC:

1102

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0317

AC:

110

AN:

3472

East Asian (EAS)

AF:

0.0396

AC:

205

AN:

5182

South Asian (SAS)

AF:

0.0607

AC:

293

AN:

4824

European-Finnish (FIN)

AF:

0.0165

AC:

175

AN:

10630

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0341

AC:

2319

AN:

68020

Other (OTH)

AF:

0.0534

AC:

113

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

459

918

1377

1836

2295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0429

Hom.:

608

Bravo

AF:

0.0689

TwinsUK

AF:

0.0324

AC:

120

ALSPAC

AF:

0.0332

AC:

128

ESP6500AA

AF:

0.122

AC:

533

ESP6500EA

AF:

0.0336

AC:

288

ExAC

AF:

0.0525

AC:

6335

Asia WGS

AF:

0.0850

AC:

293

AN:

3478

EpiCase

AF:

0.0348

EpiControl

AF:

0.0376

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Feb 15, 2016

PreventionGenetics, part of Exact Sciences

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

- -

Dec 11, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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. -

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.36

T;.;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.68

T;T;T

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;.;.

PhyloP100

-0.41

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.9

D;.;.

REVEL

Benign

0.073

Sift

Uncertain

0.016

D;.;.

Sift4G

Benign

0.19

T;.;.

Polyphen

0.0070

B;.;.

Vest4

0.0090

MPC

0.0045

ClinPred

0.011

GERP RS

1.0

Varity_R

0.17

gMVP

0.11

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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