Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS1

The NM_173660.5(DOK7):c.202G>A(p.Gly68Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000107 in 1,611,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 5.67

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_173660.5

BP4

Computational evidence support a benign effect (MetaRNN=0.05096656).

BP6

Variant 4-3473507-G-A is Benign according to our data. Variant chr4-3473507-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465684.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000591 (90/152396) while in subpopulation AFR AF = 0.00202 (84/41598). AF 95% confidence interval is 0.00167. There are 0 homozygotes in GnomAd4. There are 42 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
DOK7	NM_173660.5	MANE Select	c.202G>A	p.Gly68Ser	missense	Exon 3 of 7	NP_775931.3
DOK7	NM_001301071.2		c.202G>A	p.Gly68Ser	missense	Exon 3 of 10	NP_001288000.1
DOK7	NM_001164673.2		c.202G>A	p.Gly68Ser	missense	Exon 3 of 7	NP_001158145.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DOK7	ENST00000340083.6	TSL:1 MANE Select	c.202G>A	p.Gly68Ser	missense	Exon 3 of 7	ENSP00000344432.5
DOK7	ENST00000507039.5	TSL:2	c.202G>A	p.Gly68Ser	missense	Exon 3 of 7	ENSP00000423614.1
DOK7	ENST00000511267.5	TSL:4	n.221G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes

AF:

0.000558

AC:

AN:

152278

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00190

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000165

AC:

AN:

247934

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.00189

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000558

Gnomad FIN exome

AF:

0.000279

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000569

AC:

AN:

1458798

Hom.:

Cov.:

AF XY:

0.0000455

AC XY:

AN XY:

725704

show subpopulations

African (AFR)

AF:

0.00141

AC:

AN:

33404

American (AMR)

AF:

0.000134

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.000209

AC:

AN:

52572

Middle Eastern (MID)

AF:

0.000238

AC:

AN:

4196

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111758

Other (OTH)

AF:

0.000266

AC:

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000591

AC:

AN:

152396

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74526

show subpopulations

African (AFR)

AF:

0.00202

AC:

AN:

41598

American (AMR)

AF:

0.0000653

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.00115

Hom.:

Bravo

AF:

0.000661

ESP6500AA

AF:

0.00190

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000149

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

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

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

M_CAP

Benign

0.057

MetaRNN

Benign

0.051

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.3

PhyloP100

5.7

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.32

Sift

Benign

0.085

Sift4G

Benign

0.083

Polyphen

0.96

Vest4

0.35

MVP

0.83

MPC

0.0047

ClinPred

0.11

GERP RS

3.7

Varity_R

0.28

gMVP

0.58

Mutation Taster

=70/30

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

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

rs376509451

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over