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.1469C>T(p.Ser490Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,609,980 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. S490W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0026 ( 4 hom., cov: 35)

Exomes 𝑓: 0.0019 ( 25 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.49

Publications

6 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=0.0022628307).

BP6

Variant 4-3493455-C-T is Benign according to our data. Variant chr4-3493455-C-T is described in ClinVar as Benign. ClinVar VariationId is 262868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00258 (393/152362) while in subpopulation EAS AF = 0.0284 (147/5180). AF 95% confidence interval is 0.0246. There are 4 homozygotes in GnomAd4. There are 210 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

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.1469C>T	p.Ser490Leu	missense	Exon 7 of 7	NP_775931.3
DOK7	NM_001301071.2		c.1469C>T	p.Ser490Leu	missense	Exon 7 of 10	NP_001288000.1
DOK7	NM_001363811.2		c.1037C>T	p.Ser346Leu	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.1469C>T	p.Ser490Leu	missense	Exon 7 of 7	ENSP00000344432.5
DOK7	ENST00000643608.1		c.1037C>T	p.Ser346Leu	missense	Exon 5 of 8	ENSP00000495701.1
DOK7	ENST00000515886.5	TSL:2	c.539C>T	p.Ser180Leu	missense	Exon 4 of 4	ENSP00000492194.1

Frequencies

GnomAD3 genomes

AF:

0.00257

AC:

392

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0285

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0124

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00528

AC:

1242

AN:

235078

AF XY:

0.00473

show subpopulations

Gnomad AFR exome

AF:

0.000864

Gnomad AMR exome

AF:

0.00470

Gnomad ASJ exome

AF:

0.000104

Gnomad EAS exome

AF:

0.0363

Gnomad FIN exome

AF:

0.0135

Gnomad NFE exome

AF:

0.000970

Gnomad OTH exome

AF:

0.00430

GnomAD4 exome

AF:

0.00185

AC:

2699

AN:

1457618

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

1275

AN XY:

724860

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33412

American (AMR)

AF:

0.00438

AC:

195

AN:

44522

Ashkenazi Jewish (ASJ)

AF:

0.0000768

AC:

AN:

26052

East Asian (EAS)

AF:

0.0270

AC:

1070

AN:

39582

South Asian (SAS)

AF:

0.000816

AC:

AN:

85790

European-Finnish (FIN)

AF:

0.0144

AC:

742

AN:

51612

Middle Eastern (MID)

AF:

0.000525

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.000420

AC:

467

AN:

1110738

Other (OTH)

AF:

0.00233

AC:

140

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

173

345

518

690

863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00258

AC:

393

AN:

152362

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

210

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41592

American (AMR)

AF:

0.00294

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0284

AC:

147

AN:

5180

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0124

AC:

132

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

68034

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00186

Hom.:

Bravo

AF:

0.00240

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000499

AC:

ExAC

AF:

0.00474

AC:

569

Asia WGS

AF:

0.00808

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Fetal akinesia deformation sequence 3 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.10

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

2.5

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.1

REVEL

Benign

0.049

Sift

Benign

0.22

Sift4G

Benign

0.096

Polyphen

0.0010

Vest4

0.18

MVP

0.54

MPC

0.0048

ClinPred

0.0041

GERP RS

1.0

Varity_R

0.064

gMVP

0.13

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_173660.5:c.1469C>T

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over