NM_173660.5:c.781C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_173660.5(DOK7):c.781C>T(p.Arg261Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,612,640 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts 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. R261H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00079 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00045 ( 2 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.788

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008238316).

BP6

Variant 4-3492767-C-T is Benign according to our data. Variant chr4-3492767-C-T is described in ClinVar as [Benign]. Clinvar id is 423589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5 link	c.781C>T	p.Arg261Cys	missense_variant	Exon 7 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.781C>T	p.Arg261Cys	missense_variant	Exon 7 of 7	1	NM_173660.5	ENSP00000344432.5		Q18PE1-1

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

121

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.0109

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000840

AC:

208

AN:

247490

Hom.:

AF XY:

0.000869

AC XY:

117

AN XY:

134584

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.0110

Gnomad EAS exome

AF:

0.000709

Gnomad SAS exome

AF:

0.000915

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000254

Gnomad OTH exome

AF:

0.000822

GnomAD4 exome

AF:

0.000445

AC:

650

AN:

1460372

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

351

AN XY:

726516

show subpopulations

Gnomad4 AFR exome

AF:

0.000896

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.0114

Gnomad4 EAS exome

AF:

0.000327

Gnomad4 SAS exome

AF:

0.000649

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000154

Gnomad4 OTH exome

AF:

0.00109

GnomAD4 genome

AF:

0.000795

AC:

121

AN:

152268

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.0109

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000662

Hom.:

Bravo

AF:

0.000744

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000693

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 20, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DOK7-related disorder

Benign:1

Feb 25, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

T;.

Eigen

Benign

0.025

Eigen_PC

Benign

-0.0040

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.0082

T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-4.6

D;.

REVEL

Uncertain

0.35

Sift

Uncertain

0.018

D;.

Sift4G

Uncertain

0.034

D;.

Polyphen

1.0

D;.

Vest4

0.39

MVP

0.80

MPC

0.0043

ClinPred

0.051

GERP RS

1.9

Varity_R

0.22

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over