chr4-3493166-G-A

Position:

chr4-3493166-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_173660.5(DOK7):c.1180G>A(p.Glu394Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,607,502 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.54

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5 linkuse as main transcript	c.1180G>A	p.Glu394Lys	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.1180G>A	p.Glu394Lys	missense_variant	7/7	1	NM_173660.5	ENSP00000344432	P1	Q18PE1-1
DOK7	ENST00000643608.1 linkuse as main transcript	c.748G>A	p.Glu250Lys	missense_variant	5/8			ENSP00000495701
DOK7	ENST00000515886.5 linkuse as main transcript	c.250G>A	p.Glu84Lys	missense_variant	4/4	2		ENSP00000492194
DOK7	ENST00000507039.5 linkuse as main transcript	c.*401G>A		3_prime_UTR_variant	7/7	2		ENSP00000423614		Q18PE1-4

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000302

AC:

AN:

231704

Hom.:

AF XY:

0.0000473

AC XY:

AN XY:

126922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000574

Gnomad SAS exome

AF:

0.000101

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000293

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000275

AC:

AN:

1455304

Hom.:

Cov.:

114

AF XY:

0.0000332

AC XY:

AN XY:

723724

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.000105

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000665

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000339

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000332

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.1180G>A (p.E394K) alteration is located in exon 7 (coding exon 7) of the DOK7 gene. This alteration results from a G to A substitution at nucleotide position 1180, causing the glutamic acid (E) at amino acid position 394 to be replaced by a lysine (K). 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

Jun 09, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 394 of the DOK7 protein (p.Glu394Lys). This variant is present in population databases (rs751691265, gnomAD 0.01%). 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: 534115). 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

Benign

0.15

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

T;.;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.69

T;T;T

M_CAP

Pathogenic

0.30

MetaRNN

Uncertain

0.53

D;D;D

MetaSVM

Uncertain

0.0048

MutationAssessor

Uncertain

2.5

M;.;.

MutationTaster

Benign

0.67

D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.8

D;.;.

REVEL

Uncertain

0.41

Sift

Uncertain

0.0060

D;.;.

Sift4G

Benign

0.11

T;.;.

Polyphen

0.98

D;.;.

Vest4

0.63

MVP

0.82

MPC

0.019

ClinPred

0.51

GERP RS

3.8

Varity_R

0.16

gMVP

0.51

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