chr4-3489685-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_173660.5(DOK7):c.661C>G(p.Pro221Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,565,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P221S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.0130

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: 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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043099046).

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.661C>G	p.Pro221Ala	missense	Exon 6 of 7	NP_775931.3
DOK7	NM_001301071.2		c.661C>G	p.Pro221Ala	missense	Exon 6 of 10	NP_001288000.1	Q18PE1-3
DOK7	NM_001363811.2		c.229C>G	p.Pro77Ala	missense	Exon 4 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.661C>G	p.Pro221Ala	missense	Exon 6 of 7	ENSP00000344432.5	Q18PE1-1
DOK7	ENST00000513995.1	TSL:1	n.319C>G		non_coding_transcript_exon	Exon 2 of 3
DOK7	ENST00000643608.1		c.229C>G	p.Pro77Ala	missense	Exon 4 of 8	ENSP00000495701.1	A0A2R8Y701

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000748

AC:

AN:

173762

AF XY:

0.0000755

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000743

Gnomad ASJ exome

AF:

0.000806

Gnomad EAS exome

AF:

0.0000774

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000284

Gnomad OTH exome

AF:

0.000213

GnomAD4 exome

AF:

0.0000184

AC:

AN:

1413220

Hom.:

Cov.:

AF XY:

0.0000172

AC XY:

AN XY:

698592

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32276

American (AMR)

AF:

0.0000527

AC:

AN:

37980

Ashkenazi Jewish (ASJ)

AF:

0.000672

AC:

AN:

25280

East Asian (EAS)

AF:

0.0000271

AC:

AN:

36834

South Asian (SAS)

AF:

0.00

AC:

AN:

80324

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49084

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.00000368

AC:

AN:

1087240

Other (OTH)

AF:

0.0000342

AC:

AN:

58526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.0000263

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41402

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.0000254

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000170

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.38

CADD

Benign

4.9

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.046

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.0085

LIST_S2

Benign

0.63

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.043

MetaSVM

Uncertain

-0.25

PhyloP100

-0.013

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.72

REVEL

Benign

0.11

Sift

Benign

0.30

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.21

MutPred

0.34

Loss of glycosylation at P222 (P = 0.0042)

MVP

0.81

MPC

0.0046

ClinPred

0.039

GERP RS

0.43

Varity_R

0.023

gMVP

0.22

Mutation Taster

=95/5

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