rs199578351

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_173660.5(DOK7):c.332-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,384,606 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 42 hom., cov: 30)

Exomes 𝑓: 0.00081 ( 25 hom. )

Consequence

DOK7
NM_173660.5 splice_region, intron

Scores

Splicing: ADA: 0.00002415

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.89

Publications

2 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:

LOC105374355 (HGNC:):

LOC105374355 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 4-3476338-G-A is Benign according to our data. Variant chr4-3476338-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00733 (950/129618) while in subpopulation AFR AF = 0.0265 (909/34348). AF 95% confidence interval is 0.025. There are 42 homozygotes in GnomAd4. There are 457 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5 link	c.332-4G>A		splice_region_variant, intron_variant	Intron 3 of 6	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6 link	c.332-4G>A		splice_region_variant, intron_variant	Intron 3 of 6	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes

AF:

0.00731

AC:

947

AN:

129540

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0264

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00285

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000282

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000161

Gnomad OTH

AF:

0.00352

GnomAD2 exomes

AF:

0.00201

AC:

481

AN:

239618

AF XY:

0.00129

show subpopulations

Gnomad AFR exome

AF:

0.0294

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000924

Gnomad OTH exome

AF:

0.000344

GnomAD4 exome

AF:

0.000811

AC:

1018

AN:

1254988

Hom.:

Cov.:

AF XY:

0.000681

AC XY:

424

AN XY:

622268

show subpopulations

African (AFR)

AF:

0.0299

AC:

827

AN:

27674

American (AMR)

AF:

0.00182

AC:

AN:

38494

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17862

East Asian (EAS)

AF:

0.00

AC:

AN:

25054

South Asian (SAS)

AF:

0.0000713

AC:

AN:

84152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33922

Middle Eastern (MID)

AF:

0.000650

AC:

AN:

4612

European-Non Finnish (NFE)

AF:

0.00000921

AC:

AN:

976690

Other (OTH)

AF:

0.00221

AC:

103

AN:

46528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.594

Heterozygous variant carriers

129

161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00733

AC:

950

AN:

129618

Hom.:

Cov.:

AF XY:

0.00736

AC XY:

457

AN XY:

62078

show subpopulations

African (AFR)

AF:

0.0265

AC:

909

AN:

34348

American (AMR)

AF:

0.00284

AC:

AN:

11600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3212

East Asian (EAS)

AF:

0.00

AC:

AN:

4140

South Asian (SAS)

AF:

0.000282

AC:

AN:

3544

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7724

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000161

AC:

AN:

62244

Other (OTH)

AF:

0.00348

AC:

AN:

1724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.536

Heterozygous variant carriers

107

142

178

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00330

Hom.:

Bravo

AF:

0.00835

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jul 26, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.82

(source)

DANN

Benign

0.73

PhyloP100

-1.9

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000024

dbscSNV1_RF

Benign

0.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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