Variant 4-3463421-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_173660.5(DOK7):c.46G>T(p.Gly16Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000459 in 1,306,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G16G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000046 ( 0 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.06

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 Uncertain_significance. Variant got 4 ACMG points.

PM1

In a domain PH (size 105) in uniprot entity DOK7_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_173660.5

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.46G>T	p.Gly16Cys	missense_variant	1/7	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.46G>T	p.Gly16Cys	missense_variant	1/7	1	NM_173660.5	ENSP00000344432.5		Q18PE1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000112

AC:

AN:

89144

Hom.:

AF XY:

0.00

AC XY:

AN XY:

50858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000830

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:

0.00000459

AC:

AN:

1306786

Hom.:

Cov.:

AF XY:

0.00000310

AC XY:

AN XY:

645582

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000429

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:

0.00000479

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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

Aug 21, 2023

The c.46G>T (p.G16C) alteration is located in exon 1 (coding exon 1) of the DOK7 gene. This alteration results from a G to T substitution at nucleotide position 46, causing the glycine (G) at amino acid position 16 to be replaced by a cysteine (C). 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

Uncertain

0.54

BayesDel_addAF

Benign

0.0086

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

.;T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Uncertain

0.71

D;D;D

MetaSVM

Uncertain

0.25

MutationAssessor

Uncertain

2.3

M;M;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.6

D;D;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.011

D;D;.

Polyphen

1.0

.;D;.

Vest4

0.49

MutPred

0.44

Gain of glycosylation at S21 (P = 0.0131);Gain of glycosylation at S21 (P = 0.0131);Gain of glycosylation at S21 (P = 0.0131);

MVP

0.90

MPC

0.018

ClinPred

0.98

GERP RS

2.3

Varity_R

0.66

gMVP

0.68

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