Genetic Variant DOK7:p.Ser439Ser (chr4-3493303-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.1317C>T(p.Ser439Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,606,308 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S439S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 52 hom., cov: 34)

Exomes 𝑓: 0.0017 ( 42 hom. )

Consequence

DOK7
NM_173660.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.309

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: 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=-0.82).

BP6

Variant 4-3493303-C-T is Benign according to our data. Variant chr4-3493303-C-T is described in ClinVar as Benign. ClinVar VariationId is 128909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.309 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1991/152342) while in subpopulation AFR AF = 0.0448 (1864/41562). AF 95% confidence interval is 0.0432. There are 52 homozygotes in GnomAd4. There are 961 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 52 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.1317C>T	p.Ser439Ser	synonymous	Exon 7 of 7	NP_775931.3
DOK7	NM_001301071.2		c.1317C>T	p.Ser439Ser	synonymous	Exon 7 of 10	NP_001288000.1	Q18PE1-3
DOK7	NM_001363811.2		c.885C>T	p.Ser295Ser	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.1317C>T	p.Ser439Ser	synonymous	Exon 7 of 7	ENSP00000344432.5	Q18PE1-1
DOK7	ENST00000643608.1		c.885C>T	p.Ser295Ser	synonymous	Exon 5 of 8	ENSP00000495701.1	A0A2R8Y701
DOK7	ENST00000515886.5	TSL:2	c.387C>T	p.Ser129Ser	synonymous	Exon 4 of 4	ENSP00000492194.1	A0A1W2PRA3

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1986

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0449

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00764

GnomAD2 exomes

AF:

0.00349

AC:

777

AN:

222354

AF XY:

0.00266

show subpopulations

Gnomad AFR exome

AF:

0.0493

Gnomad AMR exome

AF:

0.00316

Gnomad ASJ exome

AF:

0.000108

Gnomad EAS exome

AF:

0.000293

Gnomad FIN exome

AF:

0.0000508

Gnomad NFE exome

AF:

0.000261

Gnomad OTH exome

AF:

0.00127

GnomAD4 exome

AF:

0.00169

AC:

2456

AN:

1453966

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1071

AN XY:

722622

show subpopulations

African (AFR)

AF:

0.0503

AC:

1676

AN:

33336

American (AMR)

AF:

0.00304

AC:

134

AN:

44058

Ashkenazi Jewish (ASJ)

AF:

0.0000386

AC:

AN:

25890

East Asian (EAS)

AF:

0.000330

AC:

AN:

39406

South Asian (SAS)

AF:

0.000246

AC:

AN:

85502

European-Finnish (FIN)

AF:

0.0000391

AC:

AN:

51162

Middle Eastern (MID)

AF:

0.00418

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000390

AC:

432

AN:

1108868

Other (OTH)

AF:

0.00255

AC:

153

AN:

59996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

165

330

496

661

826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.0131

AC:

1991

AN:

152342

Hom.:

Cov.:

AF XY:

0.0129

AC XY:

961

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0448

AC:

1864

AN:

41562

American (AMR)

AF:

0.00509

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68028

Other (OTH)

AF:

0.00756

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

198

296

395

494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.0154

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.4

(source)

DANN

Benign

0.57

PhyloP100

-0.31

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