4-3476324-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_173660.5(DOK7):c.332-18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 775,664 control chromosomes in the GnomAD database, including 27,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 5709 hom., cov: 17)

Exomes 𝑓: 0.14 ( 22216 hom. )

Consequence

DOK7
NM_173660.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.50

Publications

8 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
fetal akinesia deformation sequence 3
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
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=-0.87).

BP6

Variant 4-3476324-T-C is Benign according to our data. Variant chr4-3476324-T-C is described in ClinVar as Benign. ClinVar VariationId is 262875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.344 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DOK7	NM_173660.5	MANE Select	c.332-18T>C	intron	N/A	NP_775931.3
DOK7	NM_001301071.2		c.332-18T>C	intron	N/A	NP_001288000.1	Q18PE1-3
DOK7	NM_001363811.2		c.101-9215T>C	intron	N/A	NP_001350740.1	A0A2R8Y701

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DOK7	ENST00000340083.6	TSL:1 MANE Select	c.332-18T>C	intron	N/A	ENSP00000344432.5	Q18PE1-1
DOK7	ENST00000643608.1		c.101-9215T>C	intron	N/A	ENSP00000495701.1	A0A2R8Y701
DOK7	ENST00000507039.5	TSL:2	c.332-18T>C	intron	N/A	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes

AF:

0.283

AC:

25727

AN:

91024

Hom.:

5697

Cov.:

show subpopulations

Gnomad AFR

AF:

0.351

Gnomad AMI

AF:

0.0787

Gnomad AMR

AF:

0.327

Gnomad ASJ

AF:

0.228

Gnomad EAS

AF:

0.269

Gnomad SAS

AF:

0.263

Gnomad FIN

AF:

0.199

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.261

Gnomad OTH

AF:

0.298

GnomAD2 exomes

AF:

0.0321

AC:

3026

AN:

94144

AF XY:

0.0289

show subpopulations

Gnomad AFR exome

AF:

0.0899

Gnomad AMR exome

AF:

0.0429

Gnomad ASJ exome

AF:

0.0231

Gnomad EAS exome

AF:

0.0198

Gnomad FIN exome

AF:

0.0282

Gnomad NFE exome

AF:

0.0288

Gnomad OTH exome

AF:

0.0288

GnomAD4 exome

AF:

0.140

AC:

96084

AN:

684598

Hom.:

22216

Cov.:

AF XY:

0.145

AC XY:

49720

AN XY:

342088

show subpopulations

African (AFR)

AF:

0.240

AC:

2761

AN:

11522

American (AMR)

AF:

0.324

AC:

7731

AN:

23838

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

1575

AN:

11692

East Asian (EAS)

AF:

0.237

AC:

5979

AN:

25240

South Asian (SAS)

AF:

0.234

AC:

9902

AN:

42316

European-Finnish (FIN)

AF:

0.136

AC:

3820

AN:

28106

Middle Eastern (MID)

AF:

0.150

AC:

382

AN:

2544

European-Non Finnish (NFE)

AF:

0.117

AC:

60116

AN:

511864

Other (OTH)

AF:

0.139

AC:

3818

AN:

27476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

2977

5955

8932

11910

14887

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1368

2736

4104

5472

6840

<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:

0.283

AC:

25759

AN:

91066

Hom.:

5709

Cov.:

AF XY:

0.284

AC XY:

12591

AN XY:

44320

show subpopulations

African (AFR)

AF:

0.351

AC:

7330

AN:

20910

American (AMR)

AF:

0.327

AC:

2948

AN:

9026

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

461

AN:

2022

East Asian (EAS)

AF:

0.269

AC:

1106

AN:

4110

South Asian (SAS)

AF:

0.266

AC:

669

AN:

2516

European-Finnish (FIN)

AF:

0.199

AC:

1387

AN:

6962

Middle Eastern (MID)

AF:

0.307

AC:

AN:

176

European-Non Finnish (NFE)

AF:

0.261

AC:

11384

AN:

43544

Other (OTH)

AF:

0.305

AC:

375

AN:

1228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

611

1222

1832

2443

3054

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

238

476

714

952

1190

<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:

0.404

Hom.:

2888

Bravo

AF:

0.425

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Congenital myasthenic syndrome 10 (1)

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

Fetal akinesia deformation sequence 3 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.51

(source)

DANN

Benign

0.38

PhyloP100

-2.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over