rs6811856

Positions:

• chr4-3493099-A-C
• chr4-3493099-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_173660.5(DOK7):​c.1113A>C​(p.Ser371=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,579,746 control chromosomes in the GnomAD database, including 40,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3574 hom., cov: 34)
  • Exomes 𝑓: 0.22 (36706 hom.)
• Consequence: DOK7 NM_173660.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.44

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 4-3493099-A-C is Benign according to our data. Variant chr4-3493099-A-C is described in ClinVar as [Benign]. Clinvar id is 128904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3493099-A-C is described in Lovd as [Benign]. Variant chr4-3493099-A-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5	c.1113A>C	p.Ser371=	synonymous_variant	7/7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.1113A>C	p.Ser371=	synonymous_variant	7/7	1	NM_173660.5	ENSP00000344432	P1
DOK7	ENST00000643608.1	c.681A>C	p.Ser227=	synonymous_variant	5/8			ENSP00000495701
DOK7	ENST00000515886.5	c.183A>C	p.Ser61=	synonymous_variant	4/4	2		ENSP00000492194
DOK7	ENST00000507039.5	c.*334A>C		3_prime_UTR_variant	7/7	2		ENSP00000423614

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28587 AN: 152040 Hom.: 3579 Cov.: 34

Gnomad AFR AF: 0.0557

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.191

GnomAD3 exomes AF: 0.224 AC: 42420 AN: 189222 Hom.: 5618 AF XY: 0.227 AC XY: 23580 AN XY: 104016

Gnomad AFR exome AF: 0.0524

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.489

Gnomad SAS exome AF: 0.213

Gnomad FIN exome AF: 0.380

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.217 AC: 309943 AN: 1427588 Hom.: 36706 Cov.: 110 AF XY: 0.217 AC XY: 154015 AN XY: 708228

Gnomad4 AFR exome AF: 0.0481

Gnomad4 AMR exome AF: 0.143

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.507

Gnomad4 SAS exome AF: 0.209

Gnomad4 FIN exome AF: 0.381

Gnomad4 NFE exome AF: 0.209

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.188 AC: 28585 AN: 152158 Hom.: 3574 Cov.: 34 AF XY: 0.195 AC XY: 14505 AN XY: 74388

Gnomad4 AFR AF: 0.0556

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.211

Gnomad4 EAS AF: 0.514

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.385

Gnomad4 NFE AF: 0.216

Gnomad4 OTH AF: 0.191

Alfa AF: 0.193 Hom.: 2595

Bravo AF: 0.166

Asia WGS AF: 0.366 AC: 1273 AN: 3476

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	GeneDx	Feb 05, 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	Eurofins Ntd Llc (ga)	Nov 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 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
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.38
DANN	Benign	0.59

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: rs6811856; hg19: chr4-3494826; COSMIC: COSV60772560; COSMIC: COSV60772560;