rs16844470

Positions:

chr4-3493337-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.1351C>T(p.Arg451Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,600,082 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 34 hom., cov: 34)

Exomes 𝑓: 0.0022 ( 45 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.02

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=0.0030781329).

BP6

Variant 4-3493337-C-T is Benign according to our data. Variant chr4-3493337-C-T is described in ClinVar as [Benign]. Clinvar id is 128910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3493337-C-T is described in Lovd as [Likely_benign]. Variant chr4-3493337-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0135 (2052/152308) while in subpopulation AFR AF= 0.0432 (1798/41578). AF 95% confidence interval is 0.0416. There are 34 homozygotes in gnomad4. There are 944 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5 linkuse as main transcript	c.1351C>T	p.Arg451Trp	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.1351C>T	p.Arg451Trp	missense_variant	7/7	1	NM_173660.5	ENSP00000344432.5	Q18PE1-1
DOK7	ENST00000643608.1 linkuse as main transcript	c.919C>T	p.Arg307Trp	missense_variant	5/8			ENSP00000495701.1	A0A2R8Y701
DOK7	ENST00000515886.5 linkuse as main transcript	c.421C>T	p.Arg141Trp	missense_variant	4/4	2		ENSP00000492194.1	A0A1W2PRA3
DOK7	ENST00000507039.5 linkuse as main transcript	c.*572C>T		3_prime_UTR_variant	7/7	2		ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes

AF:

0.0135

AC:

2048

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0433

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00949

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00128

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00362

AC:

773

AN:

213460

Hom.:

AF XY:

0.00309

AC XY:

365

AN XY:

118078

show subpopulations

Gnomad AFR exome

AF:

0.0433

Gnomad AMR exome

AF:

0.00419

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000418

Gnomad FIN exome

AF:

0.000105

Gnomad NFE exome

AF:

0.000998

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00219

AC:

3165

AN:

1447774

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

1510

AN XY:

718856

show subpopulations

Gnomad4 AFR exome

AF:

0.0404

Gnomad4 AMR exome

AF:

0.00413

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.000507

Gnomad4 FIN exome

AF:

0.0000592

Gnomad4 NFE exome

AF:

0.00123

Gnomad4 OTH exome

AF:

0.00385

GnomAD4 genome

AF:

0.0135

AC:

2052

AN:

152308

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

944

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0432

Gnomad4 AMR

AF:

0.00948

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00128

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00494

Hom.:

Bravo

AF:

0.0152

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.0409

AC:

173

ESP6500EA

AF:

0.00132

AC:

ExAC

AF:

0.00371

AC:

437

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2014	- -

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 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;.;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.82

T;T;T

MetaRNN

Benign

0.0031

T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.1

M;.;.

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.8

D;.;.

REVEL

Benign

0.15

Sift

Uncertain

0.010

D;.;.

Sift4G

Uncertain

0.021

D;.;.

Polyphen

0.27

B;.;.

Vest4

0.32

MVP

0.77

MPC

0.019

ClinPred

0.024

GERP RS

2.5

Varity_R

0.16

gMVP

0.15

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