NM_173660.5:c.161G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_173660.5(DOK7):​c.161G>T​(p.Arg54Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,610,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R54H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

4
12
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.02

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DOK7NM_173660.5 linkc.161G>T p.Arg54Leu missense_variant Exon 3 of 7 ENST00000340083.6 NP_775931.3 Q18PE1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DOK7ENST00000340083.6 linkc.161G>T p.Arg54Leu missense_variant Exon 3 of 7 1 NM_173660.5 ENSP00000344432.5 Q18PE1-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152258
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000282
AC:
7
AN:
247908
AF XY:
0.0000444
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000390
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000110
AC:
16
AN:
1458704
Hom.:
0
Cov.:
33
AF XY:
0.0000110
AC XY:
8
AN XY:
725664
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33404
American (AMR)
AF:
0.00
AC:
0
AN:
44710
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26120
East Asian (EAS)
AF:
0.000151
AC:
6
AN:
39684
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86168
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52532
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4180
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111708
Other (OTH)
AF:
0.000166
AC:
10
AN:
60198
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.494
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000131
AC:
2
AN:
152258
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
74392
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41466
American (AMR)
AF:
0.0000654
AC:
1
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000192
AC:
1
AN:
5202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68038
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Sep 22, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.161G>T (p.R54L) alteration is located in exon 3 (coding exon 3) of the DOK7 gene. This alteration results from a G to T substitution at nucleotide position 161, causing the arginine (R) at amino acid position 54 to be replaced by a leucine (L). 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 24, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine with leucine at codon 54 of the DOK7 protein (p.Arg54Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs201818140, ExAC 0.04%). This variant has not been reported in the literature in individuals with DOK7-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.67
BayesDel_addAF
Benign
-0.029
T
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
.;D
Eigen
Uncertain
0.29
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.86
D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.75
D;D
MetaSVM
Benign
-0.36
T
MutationAssessor
Uncertain
2.1
M;M
PhyloP100
7.0
PrimateAI
Uncertain
0.66
T
PROVEAN
Pathogenic
-5.8
D;D
REVEL
Uncertain
0.53
Sift
Uncertain
0.0050
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
0.81
.;P
Vest4
0.82
MutPred
0.47
Gain of glycosylation at S55 (P = 0.0036);Gain of glycosylation at S55 (P = 0.0036);
MVP
0.86
MPC
0.018
ClinPred
0.71
D
GERP RS
3.7
Varity_R
0.66
gMVP
0.58
Mutation Taster
=67/33
polymorphism

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

Other links and lift over

dbSNP: rs201818140; hg19: chr4-3475193; API