rs139133047

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_173660.5(DOK7):c.577A>G(p.Ser193Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000332 in 1,607,594 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S193N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00033 ( 1 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 5.68

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 Uncertain_significance. Variant got 3 ACMG points.

PM1

In a domain IRS-type PTB (size 105) in uniprot entity DOK7_HUMAN there are 40 pathogenic changes around while only 1 benign (98%) in NM_173660.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3837803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5 linkuse as main transcript	c.577A>G	p.Ser193Gly	missense_variant	5/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6 linkuse as main transcript	c.577A>G	p.Ser193Gly	missense_variant	5/7	1	NM_173660.5	P1	Q18PE1-1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000284

AC:

AN:

246148

Hom.:

AF XY:

0.000292

AC XY:

AN XY:

133494

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000238

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000547

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000329

AC:

479

AN:

1455300

Hom.:

Cov.:

AF XY:

0.000315

AC XY:

228

AN XY:

723856

show subpopulations

Gnomad4 AFR exome

AF:

0.0000904

Gnomad4 AMR exome

AF:

0.000316

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.000393

Gnomad4 OTH exome

AF:

0.000416

GnomAD4 genome

AF:

0.000361

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000597

Hom.:

Bravo

AF:

0.000321

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000338

AC:

EpiCase

AF:

0.000276

EpiControl

AF:

0.000840

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 03, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect Observed in 0.031% (86/277520 alleles) in large population cohorts (Lek et al., 2016) Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 13, 2018	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2023

The c.577A>G (p.S193G) alteration is located in exon 5 (coding exon 5) of the DOK7 gene. This alteration results from a A to G substitution at nucleotide position 577, causing the serine (S) at amino acid position 193 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital myasthenic syndrome 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Oct 26, 2021

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 193 of the DOK7 protein (p.Ser193Gly). This variant is present in population databases (rs139133047, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with DOK7-related conditions. ClinVar contains an entry for this variant (Variation ID: 418166). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.0040

BayesDel_noAF

Benign

-0.15

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.20

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.38

MetaSVM

Uncertain

0.046

MutationTaster

Benign

0.85

D;D;N

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.52

Sift

Uncertain

0.0080

Sift4G

Benign

0.31

Vest4

0.55

MVP

0.92

ClinPred

0.44

GERP RS

3.4

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