rs62272670

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_173660.5(DOK7):c.134C>T(p.Ser45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0054 in 1,611,020 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S45S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0046 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0055 ( 59 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.707

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=0.0065547824).

BP6

Variant 4-3473439-C-T is Benign according to our data. Variant chr4-3473439-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00464 (707/152344) while in subpopulation NFE AF = 0.00523 (356/68024). AF 95% confidence interval is 0.00478. There are 1 homozygotes in GnomAd4. There are 326 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 59 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5 link	c.134C>T	p.Ser45Leu	missense_variant	Exon 3 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.134C>T	p.Ser45Leu	missense_variant	Exon 3 of 7	1	NM_173660.5	ENSP00000344432.5		Q18PE1-1

Frequencies

GnomAD3 genomes

AF:

0.00460

AC:

701

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.0461

Gnomad EAS

AF:

0.00308

Gnomad SAS

AF:

0.00289

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00523

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00550

AC:

1359

AN:

246904

AF XY:

0.00560

show subpopulations

Gnomad AFR exome

AF:

0.00182

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.0488

Gnomad EAS exome

AF:

0.00190

Gnomad FIN exome

AF:

0.000789

Gnomad NFE exome

AF:

0.00513

Gnomad OTH exome

AF:

0.00598

GnomAD4 exome

AF:

0.00548

AC:

8000

AN:

1458676

Hom.:

Cov.:

AF XY:

0.00545

AC XY:

3958

AN XY:

725696

show subpopulations

African (AFR)

AF:

0.00168

AC:

AN:

33402

American (AMR)

AF:

0.00132

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0503

AC:

1313

AN:

26120

East Asian (EAS)

AF:

0.00141

AC:

AN:

39692

South Asian (SAS)

AF:

0.00497

AC:

428

AN:

86136

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

52462

Middle Eastern (MID)

AF:

0.00409

AC:

AN:

4158

European-Non Finnish (NFE)

AF:

0.00499

AC:

5550

AN:

1111798

Other (OTH)

AF:

0.00759

AC:

457

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

474

949

1423

1898

2372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

234

468

702

936

1170

<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:

0.00464

AC:

707

AN:

152344

Hom.:

Cov.:

AF XY:

0.00438

AC XY:

326

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

41584

American (AMR)

AF:

0.000784

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0461

AC:

160

AN:

3472

East Asian (EAS)

AF:

0.00309

AC:

AN:

5184

South Asian (SAS)

AF:

0.00310

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00523

AC:

356

AN:

68024

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

120

160

200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00595

Hom.:

Bravo

AF:

0.00477

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00308

AC:

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.00511

AC:

618

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00529

EpiControl

AF:

0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

May 02, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 25, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DOK7 c.134C>T (p.Ser45Leu) results in a non-conservative amino acid change located in the Pleckstrin homology domain (IPR001849) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0055 in 246904 control chromosomes in the gnomAD database, including 19 homozygotes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in DOK7 causing Congenital Myasthenic Syndrome phenotype (0.0014), strongly suggesting that the variant is benign. c.134C>T has been reported in the literature in the heterozygous state together with the pathogenic variant c.1124_1127dupTGCC in individuals affected with Congenital Myasthenic Syndrome (example, Muller_2007, Ben Ammar_2010, Lorenzoni_2013). However, these reports do not provide unequivocal conclusions about association of the variant with Congenital Myasthenic Syndrome. At least one publication reports experimental evidence which suggests the variant has little to no impact on protein function (Cossins_2012). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two laboratories have classified the variant as benign, three as likely benign, and one as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Apr 13, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 14, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22661499, 23657916, 23452772, 20562457, 20012313, 26754003, 17439981, 31044425) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DOK7: BP4, BS2 -

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

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fetal akinesia deformation sequence 1

Benign:1

Aug 22, 2023

Mendelics

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

0.096

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

.;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.26

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.062

MetaRNN

Benign

0.0066

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.5

L;L

PhyloP100

0.71

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.6

D;D

REVEL

Benign

0.17

Sift

Benign

0.67

T;T

Sift4G

Uncertain

0.042

D;T

Polyphen

0.38

.;B

Vest4

0.54

MVP

0.78

MPC

0.0054

ClinPred

0.030

GERP RS

2.8

Varity_R

0.12

gMVP

0.23

Mutation Taster

=97/3

polymorphism

(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