Variant 4-3493166-G-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.1180G>C(p.Glu394Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,304 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: 0.0000027 ( 0 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

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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.1180G>C	p.Glu394Gln	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.1180G>C	p.Glu394Gln	missense_variant	7/7	1	NM_173660.5	ENSP00000344432.5	Q18PE1-1
DOK7	ENST00000643608.1 linkuse as main transcript	c.748G>C	p.Glu250Gln	missense_variant	5/8			ENSP00000495701.1	A0A2R8Y701
DOK7	ENST00000515886.5 linkuse as main transcript	c.250G>C	p.Glu84Gln	missense_variant	4/4	2		ENSP00000492194.1	A0A1W2PRA3
DOK7	ENST00000507039.5 linkuse as main transcript	c.*401G>C		3_prime_UTR_variant	7/7	2		ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000432

AC:

AN:

231704

Hom.:

AF XY:

0.00

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1455304

Hom.:

Cov.:

114

AF XY:

0.00000276

AC XY:

AN XY:

723724

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000508

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The c.1180G>C (p.E394Q) alteration is located in exon 7 (coding exon 7) of the DOK7 gene. This alteration results from a G to C substitution at nucleotide position 1180, causing the glutamic acid (E) at amino acid position 394 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.59

T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.50

T;T;T

MetaSVM

Uncertain

-0.061

MutationAssessor

Uncertain

2.5

M;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.9

N;.;.

REVEL

Benign

0.27

Sift

Uncertain

0.0080

D;.;.

Sift4G

Benign

0.17

T;.;.

Polyphen

1.0

D;.;.

Vest4

0.53

MutPred

0.56

Gain of glycosylation at Y395 (P = 0.0118);.;.;

MVP

0.82

MPC

0.020

ClinPred

0.78

GERP RS

3.8

Varity_R

0.13

gMVP

0.39

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