rs9684786

Positions:

• chr4-3493368-G-A
• chr4-3493368-G-C
• chr4-3493368-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173660.5(DOK7):​c.1382G>A​(p.Gly461Asp) variant causes a missense change. The variant allele was found at a frequency of 0.203 in 1,595,910 control chromosomes in the GnomAD database, including 34,550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2813 hom., cov: 34)
  • Exomes 𝑓: 0.20 (31737 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.10

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056107044).
• BP6: Variant 4-3493368-G-A is Benign according to our data. Variant chr4-3493368-G-A is described in ClinVar as [Benign]. Clinvar id is 128911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3493368-G-A is described in Lovd as [Benign]. Variant chr4-3493368-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.1382G>A	p.Gly461Asp	missense_variant	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.1382G>A	p.Gly461Asp	missense_variant	7/7	1	NM_173660.5	P1
DOK7	ENST00000643608.1	c.950G>A	p.Gly317Asp	missense_variant	5/8
DOK7	ENST00000515886.5	c.452G>A	p.Gly151Asp	missense_variant	4/4	2
DOK7	ENST00000507039.5	c.*603G>A		3_prime_UTR_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28312 AN: 152132 Hom.: 2805 Cov.: 34

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.187

GnomAD3 exomes AF: 0.207 AC: 42761 AN: 206948 Hom.: 4684 AF XY: 0.213 AC XY: 24332 AN XY: 114376

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.138

Gnomad SAS exome AF: 0.316

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.198

GnomAD4 exome AF: 0.205 AC: 295694 AN: 1443660 Hom.: 31737 Cov.: 95 AF XY: 0.209 AC XY: 149530 AN XY: 716614

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.215

Gnomad4 ASJ exome AF: 0.173

Gnomad4 EAS exome AF: 0.0912

Gnomad4 SAS exome AF: 0.319

Gnomad4 FIN exome AF: 0.150

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.197

GnomAD4 genome AF: 0.186 AC: 28335 AN: 152250 Hom.: 2813 Cov.: 34 AF XY: 0.189 AC XY: 14049 AN XY: 74448

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.228

Gnomad4 ASJ AF: 0.183

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.313

Gnomad4 FIN AF: 0.160

Gnomad4 NFE AF: 0.204

Gnomad4 OTH AF: 0.186

Alfa AF: 0.155 Hom.: 682

Bravo AF: 0.185

TwinsUK AF: 0.213 AC: 788

ALSPAC AF: 0.200 AC: 770

ESP6500AA AF: 0.116 AC: 491

ESP6500EA AF: 0.184 AC: 1533

ExAC AF: 0.189 AC: 22045

Asia WGS AF: 0.182 AC: 631 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2016	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	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Fetal akinesia deformation sequence 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.47	T;T;T
MetaRNN	Benign	0.0056	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.6	D;.;.
REVEL	Benign	0.16
Sift	Benign	0.043	D;.;.
Sift4G	Uncertain	0.014	D;.;.
Polyphen		0.0050	B;.;.
Vest4		0.067
MPC		0.0045
ClinPred		0.020	T
GERP RS		2.6
Varity_R		0.16
gMVP		0.074

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

Other links and lift over

dbSNP: rs9684786; hg19: chr4-3495095; COSMIC: COSV60771828; COSMIC: COSV60771828;