4-3492873-A-G

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.887A>G(p.Gln296Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,604,490 control chromosomes in the GnomAD database, including 41,728 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. Q296L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.19 ( 3608 hom., cov: 34)

Exomes 𝑓: 0.22 ( 38120 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.28

Publications

37 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=7.9506636E-4).

BP6

Variant 4-3492873-A-G is Benign according to our data. Variant chr4-3492873-A-G is described in ClinVar as Benign. ClinVar VariationId is 128916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173660.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DOK7	NM_173660.5	MANE Select	c.887A>G	p.Gln296Arg	missense	Exon 7 of 7	NP_775931.3
DOK7	NM_001301071.2		c.887A>G	p.Gln296Arg	missense	Exon 7 of 10	NP_001288000.1
DOK7	NM_001363811.2		c.455A>G	p.Gln152Arg	missense	Exon 5 of 8	NP_001350740.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DOK7	ENST00000340083.6	TSL:1 MANE Select	c.887A>G	p.Gln296Arg	missense	Exon 7 of 7	ENSP00000344432.5
DOK7	ENST00000513995.1	TSL:1	n.545A>G		non_coding_transcript_exon	Exon 3 of 3
DOK7	ENST00000643608.1		c.455A>G	p.Gln152Arg	missense	Exon 5 of 8	ENSP00000495701.1

Frequencies

GnomAD3 genomes

AF:

0.189

AC:

28691

AN:

152056

Hom.:

3612

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0545

Gnomad AMI

AF:

0.281

Gnomad AMR

AF:

0.156

Gnomad ASJ

AF:

0.213

Gnomad EAS

AF:

0.513

Gnomad SAS

AF:

0.227

Gnomad FIN

AF:

0.385

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.217

Gnomad OTH

AF:

0.193

GnomAD2 exomes

AF:

0.231

AC:

53336

AN:

231022

AF XY:

0.233

show subpopulations

Gnomad AFR exome

AF:

0.0521

Gnomad AMR exome

AF:

0.148

Gnomad ASJ exome

AF:

0.226

Gnomad EAS exome

AF:

0.497

Gnomad FIN exome

AF:

0.383

Gnomad NFE exome

AF:

0.215

Gnomad OTH exome

AF:

0.224

GnomAD4 exome

AF:

0.219

AC:

318440

AN:

1452316

Hom.:

38120

Cov.:

106

AF XY:

0.220

AC XY:

158534

AN XY:

721912

show subpopulations

African (AFR)

AF:

0.0471

AC:

1572

AN:

33348

American (AMR)

AF:

0.146

AC:

6413

AN:

43864

Ashkenazi Jewish (ASJ)

AF:

0.225

AC:

5832

AN:

25924

East Asian (EAS)

AF:

0.508

AC:

19962

AN:

39274

South Asian (SAS)

AF:

0.211

AC:

17931

AN:

85076

European-Finnish (FIN)

AF:

0.385

AC:

19268

AN:

50096

Middle Eastern (MID)

AF:

0.147

AC:

847

AN:

5752

European-Non Finnish (NFE)

AF:

0.211

AC:

233494

AN:

1108892

Other (OTH)

AF:

0.218

AC:

13121

AN:

60090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

18214

36428

54643

72857

91071

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8084

16168

24252

32336

40420

<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:

0.189

AC:

28694

AN:

152174

Hom.:

3608

Cov.:

AF XY:

0.196

AC XY:

14565

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0544

AC:

2261

AN:

41552

American (AMR)

AF:

0.155

AC:

2377

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.213

AC:

738

AN:

3472

East Asian (EAS)

AF:

0.512

AC:

2642

AN:

5156

South Asian (SAS)

AF:

0.228

AC:

1098

AN:

4822

European-Finnish (FIN)

AF:

0.385

AC:

4075

AN:

10582

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.217

AC:

14781

AN:

67980

Other (OTH)

AF:

0.194

AC:

410

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1131

2261

3392

4522

5653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

314

628

942

1256

1570

<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:

0.197

Hom.:

10900

Bravo

AF:

0.167

TwinsUK

AF:

0.208

AC:

771

ALSPAC

AF:

0.217

AC:

838

ESP6500AA

AF:

0.0555

AC:

244

ESP6500EA

AF:

0.207

AC:

1775

ExAC

AF:

0.218

AC:

26252

Asia WGS

AF:

0.372

AC:

1296

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Feb 19, 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.

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 21, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.17

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.35

MetaRNN

Benign

0.00080

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.1

PhyloP100

1.3

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.7

REVEL

Benign

0.071

Sift

Benign

0.22

Sift4G

Benign

0.41

Polyphen

0.0

Vest4

0.25

MPC

0.0045

ClinPred

0.0091

GERP RS

1.4

Varity_R

0.080

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over