4-3492873-A-G

Position:

chr4-3492873-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000340083.6(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. 13/20 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
ENST00000340083.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.28

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 -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 id is 128916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3492873-A-G is described in Lovd as [Benign]. Variant chr4-3492873-A-G is described in Lovd as [Likely_benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5 linkuse as main transcript	c.887A>G	p.Gln296Arg	missense_variant	7/7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6 linkuse as main transcript	c.887A>G	p.Gln296Arg	missense_variant	7/7	1	NM_173660.5	ENSP00000344432	P1	Q18PE1-1

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

GnomAD3 exomes

AF:

0.231

AC:

53336

AN:

231022

Hom.:

7217

AF XY:

0.233

AC XY:

29343

AN XY:

125936

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 SAS exome

AF:

0.218

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

Gnomad4 AFR exome

AF:

0.0471

Gnomad4 AMR exome

AF:

0.146

Gnomad4 ASJ exome

AF:

0.225

Gnomad4 EAS exome

AF:

0.508

Gnomad4 SAS exome

AF:

0.211

Gnomad4 FIN exome

AF:

0.385

Gnomad4 NFE exome

AF:

0.211

Gnomad4 OTH exome

AF:

0.218

GnomAD4 genome

AF:

0.189

AC:

28694

AN:

152174

Hom.:

3608

Cov.:

AF XY:

0.196

AC XY:

14565

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0544

Gnomad4 AMR

AF:

0.155

Gnomad4 ASJ

AF:

0.213

Gnomad4 EAS

AF:

0.512

Gnomad4 SAS

AF:

0.228

Gnomad4 FIN

AF:

0.385

Gnomad4 NFE

AF:

0.217

Gnomad4 OTH

AF:

0.194

Alfa

AF:

0.204

Hom.:

7415

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2016	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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.35

T;T

MetaRNN

Benign

0.00080

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.071

Sift

Benign

0.22

T;.

Sift4G

Benign

0.41

T;.

Polyphen

0.0

B;.

Vest4

0.25

MPC

0.0045

ClinPred

0.0091

GERP RS

1.4

Varity_R

0.080

gMVP

0.11

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

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