Genetic Variant DOK7:p.Phe182Phe (chr4-3485552-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS1

The NM_001164673.2(DOK7):c.535C>T(p.Leu179Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000228 in 1,603,904 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

DOK7
NM_001164673.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.95

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: Benign. The variant received -14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 9 uncertain in NM_001164673.2

BP4

Computational evidence support a benign effect (MetaRNN=0.010455757).

BP6

Variant 4-3485552-C-T is Benign according to our data. Variant chr4-3485552-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000138 (21/152358) while in subpopulation SAS AF = 0.00434 (21/4834). AF 95% confidence interval is 0.00291. There are 0 homozygotes in GnomAd4. There are 13 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_001164673.2. 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.546C>T	p.Phe182Phe	synonymous	Exon 5 of 7	NP_775931.3
DOK7	NM_001164673.2		c.535C>T	p.Leu179Phe	missense	Exon 5 of 7	NP_001158145.1	Q18PE1-4
DOK7	NM_001301071.2		c.546C>T	p.Phe182Phe	synonymous	Exon 5 of 10	NP_001288000.1	Q18PE1-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOK7	ENST00000340083.6	TSL:1 MANE Select	c.546C>T	p.Phe182Phe	synonymous	Exon 5 of 7	ENSP00000344432.5	Q18PE1-1
DOK7	ENST00000513995.1	TSL:1	n.204C>T		non_coding_transcript_exon	Exon 1 of 3
DOK7	ENST00000507039.5	TSL:2	c.535C>T	p.Leu179Phe	missense	Exon 5 of 7	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000462

AC:

113

AN:

244346

AF XY:

0.000627

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000509

GnomAD4 exome

AF:

0.000237

AC:

344

AN:

1451546

Hom.:

Cov.:

AF XY:

0.000353

AC XY:

255

AN XY:

721620

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33048

American (AMR)

AF:

0.00

AC:

AN:

44058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25960

East Asian (EAS)

AF:

0.00

AC:

AN:

38912

South Asian (SAS)

AF:

0.00376

AC:

319

AN:

84900

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52508

Middle Eastern (MID)

AF:

0.000698

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00000452

AC:

AN:

1106460

Other (OTH)

AF:

0.000267

AC:

AN:

59968

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:

0.000138

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41574

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00434

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:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.0000536

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.000536

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

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)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.16

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.26

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.010

MetaSVM

Uncertain

0.38

PhyloP100

1.9

PROVEAN

Benign

-1.0

REVEL

Benign

0.27

Sift

Uncertain

0.014

Sift4G

Uncertain

0.046

Vest4

0.24

MutPred

0.22

Gain of sheet (P = 0.0827)

MVP

0.93

ClinPred

0.038

GERP RS

3.6

Mutation Taster

=91/9

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