chr4-3493358-G-GC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_173660.5(DOK7):c.1378dupC(p.Gln460ProfsTer59) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,596,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q460Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

DOK7
NM_173660.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 2.60

Publications

5 publications found

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 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

DOK7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.

PP5

Variant 4-3493358-G-GC is Pathogenic according to our data. Variant chr4-3493358-G-GC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5 link	c.1378dupC	p.Gln460ProfsTer59	frameshift_variant	Exon 7 of 7	ENST00000340083.6	NP_775931.3	Q18PE1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DOK7	ENST00000340083.6 link	c.1378dupC	p.Gln460ProfsTer59	frameshift_variant	Exon 7 of 7	1	NM_173660.5	ENSP00000344432.5	Q18PE1-1
DOK7	ENST00000643608.1 link	c.946dupC	p.Gln316ProfsTer220	frameshift_variant	Exon 5 of 8			ENSP00000495701.1	A0A2R8Y701
DOK7	ENST00000515886.5 link	c.448dupC	p.Gln150ProfsTer59	frameshift_variant	Exon 4 of 4	2		ENSP00000492194.1	A0A1W2PRA3
DOK7	ENST00000507039.5 link	c.*599dupC		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000527

AC:

AN:

208604

AF XY:

0.0000607

show subpopulations

Gnomad AFR exome

AF:

0.0000858

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000317

Gnomad NFE exome

AF:

0.0000339

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000201

AC:

AN:

1444706

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

717054

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33118

American (AMR)

AF:

0.0000235

AC:

AN:

42546

Ashkenazi Jewish (ASJ)

AF:

0.0000390

AC:

AN:

25654

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39038

South Asian (SAS)

AF:

0.0000355

AC:

AN:

84608

European-Finnish (FIN)

AF:

0.000139

AC:

AN:

50392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.0000127

AC:

AN:

1104086

Other (OTH)

AF:

0.0000168

AC:

AN:

59546

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000718

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Mar 07, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein elongation, as the last 45 amino acids are replaced with 58 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 32360404, Jadhav2019[casereport], 34418069, 33820833, 36308527, 28508085, 16917026, 18626973) -

Aug 13, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PM3_strong, PS4_moderate, PVS1_strong -

Dec 27, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DOK7: PP1:Strong, PM2, PVS1:Moderate, PP4, PS3:Supporting -

Congenital myasthenic syndrome 10

Pathogenic:2

Jul 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 27, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fetal akinesia deformation sequence 3

Pathogenic:2

Dec 12, 2022

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 18, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:1

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change results in a frameshift in the DOK7 gene (p.Gln460Profs*59). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the DOK7 protein and extend the protein by 13 additional amino acid residues. This variant is present in population databases (rs747302811, gnomAD 0.03%). This frameshift has been observed in individuals with congenital myasthenic syndrome (PMID: 16917026, 18626973). ClinVar contains an entry for this variant (Variation ID: 1282). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects DOK7 function (PMID: 18626973). This variant results in an extension of the DOK7 protein. Other variant(s) that result in a similarly extended protein product (p.Pro504Serfs*15) have been observed in individuals with DOK7-related disease (PMID: 16917026). This suggests that these extensions may be clinically significant. For these reasons, this variant has been classified as Pathogenic. -

See cases

Pathogenic:1

Sep 05, 2024

Institute of Human Genetics, University Hospital Muenster

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG categories: PVS1_mod,PS3,PS4,PM2_sup -

Congenital myasthenic syndrome

Pathogenic:1

Jun 16, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DOK7 c.1378dupC (p.Gln460ProfsX59) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 5.3e-05 in 208604 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in DOK7 causing Congenital Myasthenic Syndrome (5.3e-05 vs 0.0014), allowing no conclusion about variant significance. c.1378dupC has been observed in individuals affected with Congenital Myasthenic Syndrome (example: Smeets_2024, Muller_2007). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 38964204, 17439981). ClinVar contains an entry for this variant (Variation ID: 1282). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.6

Mutation Taster

=8/192

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over