rs199980106

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_173660.5(DOK7):​c.178G>A​(p.Glu60Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000756 in 1,611,234 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 34)
Exomes 𝑓: 0.00062 ( 4 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

8
11

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.40
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1
In a domain PH (size 105) in uniprot entity DOK7_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_173660.5
BP4
Computational evidence support a benign effect (MetaRNN=0.011557132).
BP6
Variant 4-3473483-G-A is Benign according to our data. Variant chr4-3473483-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 465683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00205 (313/152392) while in subpopulation AFR AF= 0.00433 (180/41598). AF 95% confidence interval is 0.00381. There are 1 homozygotes in gnomad4. There are 150 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DOK7NM_173660.5 linkuse as main transcriptc.178G>A p.Glu60Lys missense_variant 3/7 ENST00000340083.6 NP_775931.3 Q18PE1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DOK7ENST00000340083.6 linkuse as main transcriptc.178G>A p.Glu60Lys missense_variant 3/71 NM_173660.5 ENSP00000344432.5 Q18PE1-1

Frequencies

GnomAD3 genomes
AF:
0.00206
AC:
314
AN:
152274
Hom.:
1
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00436
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00314
Gnomad ASJ
AF:
0.0196
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000176
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.00119
AC:
296
AN:
248224
Hom.:
2
AF XY:
0.00107
AC XY:
145
AN XY:
135140
show subpopulations
Gnomad AFR exome
AF:
0.00422
Gnomad AMR exome
AF:
0.00133
Gnomad ASJ exome
AF:
0.0147
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000259
Gnomad OTH exome
AF:
0.00149
GnomAD4 exome
AF:
0.000620
AC:
905
AN:
1458842
Hom.:
4
Cov.:
33
AF XY:
0.000634
AC XY:
460
AN XY:
725730
show subpopulations
Gnomad4 AFR exome
AF:
0.00494
Gnomad4 AMR exome
AF:
0.00150
Gnomad4 ASJ exome
AF:
0.0159
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000130
Gnomad4 OTH exome
AF:
0.00179
GnomAD4 genome
AF:
0.00205
AC:
313
AN:
152392
Hom.:
1
Cov.:
34
AF XY:
0.00201
AC XY:
150
AN XY:
74526
show subpopulations
Gnomad4 AFR
AF:
0.00433
Gnomad4 AMR
AF:
0.00313
Gnomad4 ASJ
AF:
0.0196
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.00236
Alfa
AF:
0.00118
Hom.:
1
Bravo
AF:
0.00230
ESP6500AA
AF:
0.00425
AC:
18
ESP6500EA
AF:
0.000947
AC:
8
ExAC
AF:
0.00101
AC:
122
EpiCase
AF:
0.000545
EpiControl
AF:
0.000415

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 09, 2017This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
DOK7-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 14, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.21
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.31
.;T
Eigen
Benign
0.088
Eigen_PC
Benign
0.16
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.012
T;T
MetaSVM
Benign
-0.30
T
MutationAssessor
Uncertain
2.1
M;M
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-3.0
D;D
REVEL
Uncertain
0.34
Sift
Benign
0.14
T;T
Sift4G
Benign
0.076
T;D
Polyphen
0.41
.;B
Vest4
0.70
MVP
0.80
MPC
0.0046
ClinPred
0.017
T
GERP RS
3.7
Varity_R
0.37
gMVP
0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199980106; hg19: chr4-3475210; API