4-3473601-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_173660.5(DOK7):c.296C>T(p.Ala99Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,601,886 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). Synonymous variant affecting the same amino acid position (i.e. A99A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 7.26

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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22844887).

BP6

Variant 4-3473601-C-T is Benign according to our data. Variant chr4-3473601-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262871.

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.296C>T	p.Ala99Val	missense	Exon 3 of 7	NP_775931.3
DOK7	NM_001301071.2		c.296C>T	p.Ala99Val	missense	Exon 3 of 10	NP_001288000.1	Q18PE1-3
DOK7	NM_001164673.2		c.296C>T	p.Ala99Val	missense	Exon 3 of 7	NP_001158145.1	Q18PE1-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOK7	ENST00000340083.6	TSL:1 MANE Select	c.296C>T	p.Ala99Val	missense	Exon 3 of 7	ENSP00000344432.5	Q18PE1-1
DOK7	ENST00000507039.5	TSL:2	c.296C>T	p.Ala99Val	missense	Exon 3 of 7	ENSP00000423614.1	Q18PE1-4
DOK7	ENST00000643608.1		c.100+10050C>T		intron	N/A	ENSP00000495701.1	A0A2R8Y701

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000137

AC:

AN:

234200

AF XY:

0.0000857

show subpopulations

Gnomad AFR exome

AF:

0.00141

Gnomad AMR exome

AF:

0.000150

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000385

Gnomad OTH exome

AF:

0.000349

GnomAD4 exome

AF:

0.000113

AC:

164

AN:

1449556

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

719656

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

33188

American (AMR)

AF:

0.000228

AC:

AN:

43788

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25964

East Asian (EAS)

AF:

0.00

AC:

AN:

39206

South Asian (SAS)

AF:

0.0000467

AC:

AN:

85628

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4180

European-Non Finnish (NFE)

AF:

0.0000796

AC:

AN:

1105690

Other (OTH)

AF:

0.000151

AC:

AN:

59634

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000460

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00130

AC:

AN:

41572

American (AMR)

AF:

0.000196

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.000357

Hom.:

Bravo

AF:

0.000502

ESP6500AA

AF:

0.000487

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000141

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Fetal akinesia deformation sequence 1 (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.23

MetaSVM

Uncertain

-0.035

MutationAssessor

Uncertain

2.3

PhyloP100

7.3

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.59

Sift

Benign

0.12

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.80

MVP

0.84

MPC

0.013

ClinPred

0.066

GERP RS

3.7

Varity_R

0.32

gMVP

0.57

Mutation Taster

=54/46

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.

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