Genetic Variant DOK7:p.Ser336Ser (chr4-3492994-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1

The NM_173660.5(DOK7):c.1008G>A(p.Ser336Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000381 in 1,559,344 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S336S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

DOK7
NM_173660.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.217

Publications

1 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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 4-3492994-G-A is Benign according to our data. Variant chr4-3492994-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 447278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.217 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00142 (216/152328) while in subpopulation AFR AF = 0.00493 (205/41574). AF 95% confidence interval is 0.00438. There are 1 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

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.1008G>A	p.Ser336Ser	synonymous	Exon 7 of 7	NP_775931.3
DOK7	NM_001301071.2		c.1008G>A	p.Ser336Ser	synonymous	Exon 7 of 10	NP_001288000.1	Q18PE1-3
DOK7	NM_001363811.2		c.576G>A	p.Ser192Ser	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.1008G>A	p.Ser336Ser	synonymous	Exon 7 of 7	ENSP00000344432.5	Q18PE1-1
DOK7	ENST00000643608.1		c.576G>A	p.Ser192Ser	synonymous	Exon 5 of 8	ENSP00000495701.1	A0A2R8Y701
DOK7	ENST00000515886.5	TSL:2	c.78G>A	p.Ser26Ser	synonymous	Exon 4 of 4	ENSP00000492194.1	A0A1W2PRA3

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

215

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00492

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000284

AC:

AN:

161940

AF XY:

0.000225

show subpopulations

Gnomad AFR exome

AF:

0.00431

Gnomad AMR exome

AF:

0.0000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000601

Gnomad OTH exome

AF:

0.000438

GnomAD4 exome

AF:

0.000269

AC:

378

AN:

1407016

Hom.:

Cov.:

111

AF XY:

0.000234

AC XY:

163

AN XY:

696380

show subpopulations

African (AFR)

AF:

0.00604

AC:

197

AN:

32604

American (AMR)

AF:

0.0000530

AC:

AN:

37750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25322

East Asian (EAS)

AF:

0.0000269

AC:

AN:

37108

South Asian (SAS)

AF:

0.000172

AC:

AN:

81168

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40100

Middle Eastern (MID)

AF:

0.000524

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.000128

AC:

139

AN:

1088694

Other (OTH)

AF:

0.000376

AC:

AN:

58550

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

118

147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00142

AC:

216

AN:

152328

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00493

AC:

205

AN:

41574

American (AMR)

AF:

0.000196

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.0000428

Hom.:

Bravo

AF:

0.00172

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

DOK7-related disorder (1)

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

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

6.6

(source)

DANN

Benign

0.79

PhyloP100

-0.22

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over