chr4-3493242-G-GC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_173660.5(DOK7):c.1263dupC(p.Ser422LeufsTer97) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,611,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

DOK7
NM_173660.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 0.0800

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 16 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 36 pathogenic variants in the truncated region.

PP5

Variant 4-3493242-G-GC is Pathogenic according to our data. Variant chr4-3493242-G-GC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1274.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.1263dupC	p.Ser422LeufsTer97	frameshift_variant	Exon 7 of 7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DOK7	ENST00000340083.6 link	c.1263dupC	p.Ser422LeufsTer97	frameshift_variant	Exon 7 of 7	1	NM_173660.5	ENSP00000344432.5
DOK7	ENST00000643608.1 link	c.831dupC	p.Ser278LeufsTer258	frameshift_variant	Exon 5 of 8			ENSP00000495701.1
DOK7	ENST00000515886.5 link	c.333dupC	p.Ser112LeufsTer97	frameshift_variant	Exon 4 of 4	2		ENSP00000492194.1
DOK7	ENST00000507039.5 link	c.*484dupC		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000423614.1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152192

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000758

AC:

AN:

237478

AF XY:

0.0000920

show subpopulations

Gnomad AFR exome

AF:

0.000206

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000123

AC:

179

AN:

1459632

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

726084

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51842

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000143

AC:

159

AN:

1111634

Other (OTH)

AF:

0.000116

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.000125

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000130

Hom.:

Bravo

AF:

0.000132

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fetal akinesia deformation sequence 3

Pathogenic:3

Jun 01, 2022

Solve-RD Consortium

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Sep 29, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 27, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:3

Jan 11, 2024

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 13, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_moderate, PM3_very_strong, PS4 -

Mar 07, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified with a second DOK7 variant without confirmation of phase in patients with congenital myasthenic syndromes (PMID: 16917026, 37273706, 22661499, 18626973); Frameshift variant predicted to result in protein truncation, as the last 83 amino acids are replaced with 96 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 31589614, 21850686, 18161030, 32153140, 31880392, 33726816, 16917026, 37273706, 22661499, 18626973) -

Congenital myasthenic syndrome 10

Pathogenic:2

Jun 11, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 29, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Rett syndrome

Pathogenic:1

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Congenital myasthenic syndrome 10;C4760599:Fetal akinesia deformation sequence 3

Pathogenic:1

May 31, 2024

Fulgent Genetics, Fulgent 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

Jan 12, 2025

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.Ser422Leufs*97). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 83 amino acid(s) of the DOK7 protein and extend the protein by 13 additional amino acid residues. This variant is present in population databases (rs751257124, gnomAD 0.02%). This frameshift has been observed in individual(s) with congenital myasthenic syndrome and fetal akinesia deformation sequence (PMID: 16917026, 21850686, 22661499). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1274). For these reasons, this variant has been classified as Pathogenic. -

Fetal akinesia deformation sequence 1

Pathogenic:1

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital myasthenic syndrome

Pathogenic:1

Feb 28, 2020

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.1263dupC (p.Ser422LeufsX97) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 7.6e-05 in 237478 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in DOK7 causing Congenital myasthenic syndrome (7.6e-05 vs 0.0014), allowing no conclusion about variant significance. c.1263dupC has been reported in the literature in compound heterozygous and homozygous individuals affected with Congenital myasthenic syndrome (Selcen_2008, Anderson_2008). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

DOK7-related disorder

Pathogenic:1

Dec 11, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DOK7 c.1263dupC variant is predicted to result in a frameshift and premature protein termination (p.Ser422Leufs*97). This variant has been reported in individuals with autosomal recessive congenital myasthenic syndrome (Beeson et al. 2006. PubMed ID: 16917026; Anderson et al. 2008. PubMed ID: 18161030; Cossins et al. 2012. PubMed ID: 22661499). It has also been reported in the homozygous state in a case of fetal akinesia deformation sequence (Table 1, Bruno et al. 2011. PubMed ID: 21850686). This variant is reported in 0.017% of alleles in individuals of African descent in gnomAD. Frameshift variants in DOK7 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.080

Mutation Taster

=7/193

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