rs144158112

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_173660.5(DOK7):​c.1171G>A​(p.Gly391Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,605,702 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00074 ( 1 hom., cov: 34)
Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

6
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 1.77
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 Likely_benign. Variant got -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.013844073).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DOK7NM_173660.5 linkuse as main transcriptc.1171G>A p.Gly391Arg missense_variant 7/7 ENST00000340083.6 NP_775931.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DOK7ENST00000340083.6 linkuse as main transcriptc.1171G>A p.Gly391Arg missense_variant 7/71 NM_173660.5 ENSP00000344432 P1Q18PE1-1
DOK7ENST00000643608.1 linkuse as main transcriptc.739G>A p.Gly247Arg missense_variant 5/8 ENSP00000495701
DOK7ENST00000515886.5 linkuse as main transcriptc.241G>A p.Gly81Arg missense_variant 4/42 ENSP00000492194
DOK7ENST00000507039.5 linkuse as main transcriptc.*392G>A 3_prime_UTR_variant 7/72 ENSP00000423614 Q18PE1-4

Frequencies

GnomAD3 genomes
AF:
0.000736
AC:
112
AN:
152198
Hom.:
1
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.000290
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00131
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00101
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000847
AC:
193
AN:
227988
Hom.:
0
AF XY:
0.000880
AC XY:
110
AN XY:
124986
show subpopulations
Gnomad AFR exome
AF:
0.000219
Gnomad AMR exome
AF:
0.00123
Gnomad ASJ exome
AF:
0.00105
Gnomad EAS exome
AF:
0.0000585
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000537
Gnomad NFE exome
AF:
0.00125
Gnomad OTH exome
AF:
0.00195
GnomAD4 exome
AF:
0.00107
AC:
1557
AN:
1453386
Hom.:
1
Cov.:
114
AF XY:
0.00102
AC XY:
738
AN XY:
722634
show subpopulations
Gnomad4 AFR exome
AF:
0.000270
Gnomad4 AMR exome
AF:
0.00130
Gnomad4 ASJ exome
AF:
0.00189
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000586
Gnomad4 FIN exome
AF:
0.000119
Gnomad4 NFE exome
AF:
0.00123
Gnomad4 OTH exome
AF:
0.00107
GnomAD4 genome
AF:
0.000735
AC:
112
AN:
152316
Hom.:
1
Cov.:
34
AF XY:
0.000631
AC XY:
47
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.000289
Gnomad4 AMR
AF:
0.00131
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.00101
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00101
Hom.:
0
Bravo
AF:
0.000892
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000228
AC:
1
ESP6500EA
AF:
0.00117
AC:
10
ExAC
AF:
0.000739
AC:
89

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 28, 2022In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 30, 2023- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 14, 2022The c.1171G>A (p.G391R) alteration is located in exon 7 (coding exon 7) of the DOK7 gene. This alteration results from a G to A substitution at nucleotide position 1171, causing the glycine (G) at amino acid position 391 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Congenital myasthenic syndrome 10 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJun 01, 2017- -
Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.35
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.11
T;.;.
Eigen
Benign
-0.092
Eigen_PC
Benign
-0.28
FATHMM_MKL
Benign
0.081
N
LIST_S2
Benign
0.80
T;D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Benign
0.014
T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Uncertain
2.3
M;.;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-2.5
D;.;.
REVEL
Benign
0.19
Sift
Benign
0.041
D;.;.
Sift4G
Uncertain
0.044
D;.;.
Polyphen
0.94
P;.;.
Vest4
0.18
MutPred
0.49
Gain of solvent accessibility (P = 0.0014);.;.;
MVP
0.79
MPC
0.0082
ClinPred
0.024
T
GERP RS
2.8
Varity_R
0.092
gMVP
0.36

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: rs144158112; hg19: chr4-3494884; API