rs185050737

chr4-3492994-G-Achr4-3492994-G-Cchr4-3492994-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_173660.5(DOK7):c.1008G>A(p.Ser336=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000381 in 1,559,344 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S336S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: DOK7 NM_173660.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.217

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 4-3492994-G-A is Benign according to our data. Variant chr4-3492994-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 447278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.217 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00142 (216/152328) while in subpopulation AFR AF= 0.00493 (205/41574). AF 95% confidence interval is 0.00438. There are 1 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.1008G>A	p.Ser336=	synonymous_variant	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.1008G>A	p.Ser336=	synonymous_variant	7/7	1	NM_173660.5	P1
DOK7	ENST00000643608.1	c.576G>A	p.Ser192=	synonymous_variant	5/8
DOK7	ENST00000515886.5	c.78G>A	p.Ser26=	synonymous_variant	4/4	2
DOK7	ENST00000507039.5	c.*229G>A		3_prime_UTR_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152210 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000284 AC: 46 AN: 161940 Hom.: 0 AF XY: 0.000225 AC XY: 20 AN XY: 88842

Gnomad AFR exome AF: 0.00431

Gnomad AMR exome AF: 0.0000376

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: 0.0000601

Gnomad OTH exome AF: 0.000438

GnomAD4 exome AF: 0.000269 AC: 378 AN: 1407016 Hom.: 1 Cov.: 111 AF XY: 0.000234 AC XY: 163 AN XY: 696380

Gnomad4 AFR exome AF: 0.00604

Gnomad4 AMR exome AF: 0.0000530

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000269

Gnomad4 SAS exome AF: 0.000172

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000128

Gnomad4 OTH exome AF: 0.000376

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152328 Hom.: 1 Cov.: 34 AF XY: 0.00130 AC XY: 97 AN XY: 74486

Gnomad4 AFR AF: 0.00493

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000428 Hom.: 0

Bravo AF: 0.00172

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 25, 2017

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2020

- -

DOK7-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.70
Cadd	Benign	6.6
Dann	Benign	0.79

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: rs185050737; hg19: chr4-3494721;