4-3493171-C-T

Variant names:

• chr4-3493171-C-T
• rs6850908
• NM_173660.5:c.1185C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_173660.5(DOK7):​c.1185C>T​(p.Tyr395Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,607,220 control chromosomes in the GnomAD database, including 41,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3598 hom., cov: 34)
  • Exomes 𝑓: 0.22 (38159 hom.)
• Consequence: DOK7 NM_173660.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.09
• Publications: 26 publications found

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 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• fetal akinesia deformation sequence 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 4-3493171-C-T is Benign according to our data. Variant chr4-3493171-C-T is described in ClinVar as Benign. ClinVar VariationId is 128907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173660.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.1185C>T	p.Tyr395Tyr	synonymous	Exon 7 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.1185C>T	p.Tyr395Tyr	synonymous	Exon 7 of 10	NP_001288000.1
	DOK7	NM_001363811.2		c.753C>T	p.Tyr251Tyr	synonymous	Exon 5 of 8	NP_001350740.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.1185C>T	p.Tyr395Tyr	synonymous	Exon 7 of 7	ENSP00000344432.5
	DOK7	ENST00000643608.1		c.753C>T	p.Tyr251Tyr	synonymous	Exon 5 of 8	ENSP00000495701.1
	DOK7	ENST00000515886.5	TSL:2	c.255C>T	p.Tyr85Tyr	synonymous	Exon 4 of 4	ENSP00000492194.1

Frequencies

GnomAD3 genomes AF: 0.191 AC: 28986 AN: 152096 Hom.: 3603 Cov.: 34

Gnomad AFR AF: 0.0642

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.512

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.192

GnomAD2 exomes AF: 0.231 AC: 53514 AN: 231892 AF XY: 0.232

Gnomad AFR exome AF: 0.0623

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.496

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.219 AC: 318868 AN: 1455006 Hom.: 38159 Cov.: 111 AF XY: 0.219 AC XY: 158721 AN XY: 723496

African (AFR) AF: 0.0570 AC: 1903 AN: 33372

American (AMR) AF: 0.145 AC: 6408 AN: 44132

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 5764 AN: 25994

East Asian (EAS) AF: 0.508 AC: 19999 AN: 39384

South Asian (SAS) AF: 0.210 AC: 17937 AN: 85568

European-Finnish (FIN) AF: 0.387 AC: 19669 AN: 50856

Middle Eastern (MID) AF: 0.148 AC: 851 AN: 5758

European-Non Finnish (NFE) AF: 0.210 AC: 233194 AN: 1109788

Other (OTH) AF: 0.218 AC: 13143 AN: 60154

GnomAD4 genome AF: 0.190 AC: 28988 AN: 152214 Hom.: 3598 Cov.: 34 AF XY: 0.198 AC XY: 14719 AN XY: 74430

African (AFR) AF: 0.0641 AC: 2665 AN: 41568

American (AMR) AF: 0.154 AC: 2353 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 731 AN: 3472

East Asian (EAS) AF: 0.512 AC: 2638 AN: 5154

South Asian (SAS) AF: 0.225 AC: 1086 AN: 4824

European-Finnish (FIN) AF: 0.386 AC: 4094 AN: 10602

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.216 AC: 14707 AN: 67970

Other (OTH) AF: 0.192 AC: 405 AN: 2112

Alfa AF: 0.200 Hom.: 5240

Bravo AF: 0.169

Asia WGS AF: 0.366 AC: 1275 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 05, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Nov 23, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.4
DANN	Benign	0.78
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6850908; hg19: chr4-3494898; COSMIC: COSV60774091; COSMIC: COSV60774091;