4-3492953-C-T

Position:

chr4-3492953-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_173660.5(DOK7):c.967C>T(p.Arg323Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,553,432 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R323H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0076 ( 20 hom., cov: 34)

Exomes 𝑓: 0.00082 ( 13 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.35

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067362487).

BP6

Variant 4-3492953-C-T is Benign according to our data. Variant chr4-3492953-C-T is described in ClinVar as [Benign]. Clinvar id is 128917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3492953-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00765 (1165/152338) while in subpopulation AFR AF= 0.0269 (1117/41582). AF 95% confidence interval is 0.0256. There are 20 homozygotes in gnomad4. There are 542 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5 linkuse as main transcript	c.967C>T	p.Arg323Cys	missense_variant	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6 linkuse as main transcript	c.967C>T	p.Arg323Cys	missense_variant	7/7	1	NM_173660.5	P1	Q18PE1-1
DOK7	ENST00000643608.1 linkuse as main transcript	c.535C>T	p.Arg179Cys	missense_variant	5/8
DOK7	ENST00000515886.5 linkuse as main transcript	c.37C>T	p.Arg13Cys	missense_variant	4/4	2
DOK7	ENST00000507039.5 linkuse as main transcript	c.*188C>T		3_prime_UTR_variant	7/7	2			Q18PE1-4

Frequencies

GnomAD3 genomes

AF:

0.00765

AC:

1164

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0269

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00185

AC:

283

AN:

153362

Hom.:

AF XY:

0.00146

AC XY:

122

AN XY:

83426

show subpopulations

Gnomad AFR exome

AF:

0.0296

Gnomad AMR exome

AF:

0.000979

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000172

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000189

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000908

GnomAD4 exome

AF:

0.000821

AC:

1150

AN:

1401094

Hom.:

Cov.:

111

AF XY:

0.000702

AC XY:

486

AN XY:

692378

show subpopulations

Gnomad4 AFR exome

AF:

0.0290

Gnomad4 AMR exome

AF:

0.00120

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000275

Gnomad4 SAS exome

AF:

0.0000745

Gnomad4 FIN exome

AF:

0.0000475

Gnomad4 NFE exome

AF:

0.0000480

Gnomad4 OTH exome

AF:

0.00189

GnomAD4 genome

AF:

0.00765

AC:

1165

AN:

152338

Hom.:

Cov.:

AF XY:

0.00728

AC XY:

542

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0269

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.000454

Hom.:

Bravo

AF:

0.00879

ESP6500AA

AF:

0.0231

AC:

ESP6500EA

AF:

0.000125

AC:

ExAC

AF:

0.00148

AC:

169

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;.

Eigen

Benign

0.092

Eigen_PC

Benign

-0.024

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.86

D;D;D

MetaRNN

Benign

0.0067

T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.3

M;.;.

MutationTaster

Benign

0.81

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.7

D;.;.

REVEL

Benign

0.19

Sift

Benign

0.088

T;.;.

Sift4G

Benign

0.068

T;.;.

Polyphen

0.97

D;.;.

Vest4

0.58

MVP

0.75

MPC

0.0092

ClinPred

0.020

GERP RS

4.1

Varity_R

0.24

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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