Variant chr4-3493214-A-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_173660.5(DOK7):c.1228A>C(p.Ser410Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,636 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.31

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:

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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.1228A>C	p.Ser410Arg	missense_variant	7/7	ENST00000340083.6	NP_775931.3	Q18PE1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DOK7	ENST00000340083.6 linkuse as main transcript	c.1228A>C	p.Ser410Arg	missense_variant	7/7	1	NM_173660.5	ENSP00000344432.5	Q18PE1-1
DOK7	ENST00000643608.1 linkuse as main transcript	c.796A>C	p.Ser266Arg	missense_variant	5/8			ENSP00000495701.1	A0A2R8Y701
DOK7	ENST00000515886.5 linkuse as main transcript	c.298A>C	p.Ser100Arg	missense_variant	4/4	2		ENSP00000492194.1	A0A1W2PRA3
DOK7	ENST00000507039.5 linkuse as main transcript	c.*449A>C		3_prime_UTR_variant	7/7	2		ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000416

AC:

AN:

240218

Hom.:

AF XY:

0.00000760

AC XY:

AN XY:

131528

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459636

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726104

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Sep 07, 2022

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 410 of the DOK7 protein (p.Ser410Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 581162). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The arginine 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

Uncertain

0.40

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

0.069

Eigen_PC

Benign

0.062

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.80

T;T;D

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Benign

-0.34

MutationAssessor

Uncertain

2.4

M;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.6

D;.;.

REVEL

Uncertain

0.33

Sift

Benign

0.14

T;.;.

Sift4G

Benign

0.19

T;.;.

Polyphen

0.12

B;.;.

Vest4

0.65

MutPred

0.31

Gain of glycosylation at Y405 (P = 0.0118);.;.;

MVP

0.78

MPC

0.019

ClinPred

0.90

GERP RS

3.8

Varity_R

0.51

gMVP

0.43

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