Genetic Variant DOK7:p.Pro381Pro (chr4-3493129-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_173660.5(DOK7):c.1143C>T(p.Pro381Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,594,468 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 35 hom., cov: 34)

Exomes 𝑓: 0.0021 ( 45 hom. )

Consequence

DOK7
NM_173660.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.84

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 4-3493129-C-T is Benign according to our data. Variant chr4-3493129-C-T is described in ClinVar as Benign. ClinVar VariationId is 128906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.84 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2022/152312) while in subpopulation AFR AF = 0.0433 (1798/41556). AF 95% confidence interval is 0.0416. There are 35 homozygotes in GnomAd4. There are 930 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 AR gene

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	HGVSp	Effect	Exon Rank	Protein	UniProt
DOK7	NM_173660.5	MANE Select	c.1143C>T	p.Pro381Pro	synonymous	Exon 7 of 7	NP_775931.3
DOK7	NM_001301071.2		c.1143C>T	p.Pro381Pro	synonymous	Exon 7 of 10	NP_001288000.1	Q18PE1-3
DOK7	NM_001363811.2		c.711C>T	p.Pro237Pro	synonymous	Exon 5 of 8	NP_001350740.1	A0A2R8Y701

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOK7	ENST00000340083.6	TSL:1 MANE Select	c.1143C>T	p.Pro381Pro	synonymous	Exon 7 of 7	ENSP00000344432.5	Q18PE1-1
DOK7	ENST00000643608.1		c.711C>T	p.Pro237Pro	synonymous	Exon 5 of 8	ENSP00000495701.1	A0A2R8Y701
DOK7	ENST00000515886.5	TSL:2	c.213C>T	p.Pro71Pro	synonymous	Exon 4 of 4	ENSP00000492194.1	A0A1W2PRA3

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2016

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0433

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00693

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00388

AC:

806

AN:

207784

AF XY:

0.00321

show subpopulations

Gnomad AFR exome

AF:

0.0441

Gnomad AMR exome

AF:

0.00244

Gnomad ASJ exome

AF:

0.00250

Gnomad EAS exome

AF:

0.0000645

Gnomad FIN exome

AF:

0.00101

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.00307

GnomAD4 exome

AF:

0.00215

AC:

3100

AN:

1442156

Hom.:

Cov.:

113

AF XY:

0.00212

AC XY:

1518

AN XY:

716400

show subpopulations

African (AFR)

AF:

0.0407

AC:

1349

AN:

33118

American (AMR)

AF:

0.00282

AC:

120

AN:

42552

Ashkenazi Jewish (ASJ)

AF:

0.00178

AC:

AN:

25796

East Asian (EAS)

AF:

0.0000780

AC:

AN:

38444

South Asian (SAS)

AF:

0.00183

AC:

154

AN:

84038

European-Finnish (FIN)

AF:

0.000947

AC:

AN:

47510

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00104

AC:

1146

AN:

1105338

Other (OTH)

AF:

0.00379

AC:

226

AN:

59608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

210

421

631

842

1052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<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:

0.0133

AC:

2022

AN:

152312

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

930

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0433

AC:

1798

AN:

41556

American (AMR)

AF:

0.00699

AC:

107

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00166

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00109

AC:

AN:

68022

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

103

206

309

412

515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00237

Hom.:

Bravo

AF:

0.0148

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.088

(source)

DANN

Benign

0.69

PhyloP100

-2.8

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over