4-3489776-C-T

Position:

chr4-3489776-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_173660.5(DOK7):c.752C>T(p.Ala251Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000369 in 1,572,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A251A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.361

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:

DOK7 (HGNC:):

DOK7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.019193053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5 linkuse as main transcript	c.752C>T	p.Ala251Val	missense_variant	6/7	ENST00000340083.6	NP_775931.3	Q18PE1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6 linkuse as main transcript	c.752C>T	p.Ala251Val	missense_variant	6/7	1	NM_173660.5	ENSP00000344432.5		Q18PE1-1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000109

AC:

AN:

183004

Hom.:

AF XY:

0.000123

AC XY:

AN XY:

97748

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000284

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000499

Gnomad SAS exome

AF:

0.0000818

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000397

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000317

AC:

AN:

1420378

Hom.:

Cov.:

AF XY:

0.0000313

AC XY:

AN XY:

702502

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000229

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000373

Gnomad4 SAS exome

AF:

0.0000742

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.0000510

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152020

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000330

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.000230

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000760

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 13, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.752C>T (p.A251V) alteration is located in exon 6 (coding exon 6) of the DOK7 gene. This alteration results from a C to T substitution at nucleotide position 752, causing the alanine (A) at amino acid position 251 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 251 of the DOK7 protein (p.Ala251Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 575311). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

Benign

0.074

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.59

CADD

Benign

9.4

DANN

Benign

0.85

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.11

T;T

M_CAP

Benign

0.037

MetaRNN

Benign

0.019

T;T

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.4

N;.

REVEL

Benign

0.039

Sift

Benign

0.28

T;.

Sift4G

Benign

0.27

T;.

Polyphen

0.0010

B;.

Vest4

0.14

MVP

0.38

MPC

0.0045

ClinPred

0.051

GERP RS

1.2

Varity_R

0.030

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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