4-3492890-G-C

Position:

chr4-3492890-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_173660.5(DOK7):c.904G>C(p.Ala302Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,596,382 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 34)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.87

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007143408).

BP6

Variant 4-3492890-G-C is Benign according to our data. Variant chr4-3492890-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 534133.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0022 (335/152306) while in subpopulation AFR AF= 0.0076 (316/41564). AF 95% confidence interval is 0.00691. There are 2 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5 link	c.904G>C	p.Ala302Pro	missense_variant	7/7	ENST00000340083.6	NP_775931.3	Q18PE1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6 link	c.904G>C	p.Ala302Pro	missense_variant	7/7	1	NM_173660.5	ENSP00000344432.5		Q18PE1-1

Frequencies

GnomAD3 genomes

AF:

0.00220

AC:

335

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00763

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.0000147

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000486

AC:

104

AN:

213774

Hom.:

AF XY:

0.000317

AC XY:

AN XY:

116736

show subpopulations

Gnomad AFR exome

AF:

0.00771

Gnomad AMR exome

AF:

0.0000634

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:

0.000367

GnomAD4 exome

AF:

0.000208

AC:

301

AN:

1444076

Hom.:

Cov.:

111

AF XY:

0.000149

AC XY:

107

AN XY:

717242

show subpopulations

Gnomad4 AFR exome

AF:

0.00814

Gnomad4 AMR exome

AF:

0.0000938

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:

0.000452

GnomAD4 genome

AF:

0.00220

AC:

335

AN:

152306

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00760

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000694

Hom.:

Bravo

AF:

0.00259

ESP6500AA

AF:

0.00822

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000599

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2020	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2022

The c.904G>C (p.A302P) 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 904, causing the alanine (A) at amino acid position 302 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

DOK7-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.64

T;T

MetaRNN

Benign

0.0071

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.11

Sift

Benign

0.072

T;.

Sift4G

Uncertain

0.022

D;.

Polyphen

0.0030

B;.

Vest4

0.15

MVP

0.57

MPC

0.014

ClinPred

0.037

GERP RS

1.2

Varity_R

0.33

gMVP

0.13

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