NM_173660.5:c.1225C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_173660.5(DOK7):c.1225C>T(p.Arg409Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000334 in 1,611,724 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R409H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.33

Publications

3 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5 link	c.1225C>T	p.Arg409Cys	missense_variant	Exon 7 of 7	ENST00000340083.6	NP_775931.3	Q18PE1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DOK7	ENST00000340083.6 link	c.1225C>T	p.Arg409Cys	missense_variant	Exon 7 of 7	1	NM_173660.5	ENSP00000344432.5	Q18PE1-1
DOK7	ENST00000643608.1 link	c.793C>T	p.Arg265Cys	missense_variant	Exon 5 of 8			ENSP00000495701.1	A0A2R8Y701
DOK7	ENST00000515886.5 link	c.295C>T	p.Arg99Cys	missense_variant	Exon 4 of 4	2		ENSP00000492194.1	A0A1W2PRA3
DOK7	ENST00000507039.5 link	c.*446C>T		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000603

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000296

AC:

AN:

239908

AF XY:

0.000350

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000334

Gnomad FIN exome

AF:

0.0000483

Gnomad NFE exome

AF:

0.000547

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.000334

AC:

487

AN:

1459474

Hom.:

Cov.:

AF XY:

0.000332

AC XY:

241

AN XY:

725992

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33450

American (AMR)

AF:

0.0000896

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.000126

AC:

AN:

39664

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86114

European-Finnish (FIN)

AF:

0.0000386

AC:

AN:

51828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000412

AC:

458

AN:

1111606

Other (OTH)

AF:

0.000249

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

106

141

176

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:

0.000335

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41466

American (AMR)

AF:

0.000131

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

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:

0.000583

Hom.:

Bravo

AF:

0.000310

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000315

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000714

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 03, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1225C>T (p.R409C) alteration is located in exon 7 (coding exon 7) of the DOK7 gene. This alteration results from a C to T substitution at nucleotide position 1225, causing the arginine (R) at amino acid position 409 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Sep 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 409 of the DOK7 protein (p.Arg409Cys). This variant is present in population databases (rs199606134, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with DOK7-related conditions. ClinVar contains an entry for this variant (Variation ID: 534126). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Aug 17, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;.;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.84

T;T;T

M_CAP

Pathogenic

0.49

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Uncertain

-0.069

MutationAssessor

Uncertain

2.4

M;.;.

PhyloP100

1.3

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.7

D;.;.

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

D;.;.

Sift4G

Uncertain

0.0060

D;.;.

Polyphen

1.0

D;.;.

Vest4

0.68

MVP

0.79

MPC

0.017

ClinPred

0.57

GERP RS

1.8

Varity_R

0.65

gMVP

0.49

Mutation Taster

=74/26

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over