rs144158112
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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
NM_173660.5 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 1.77
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]
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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 |
---|---|---|---|---|---|---|---|---|
DOK7 | NM_173660.5 | c.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 |
---|---|---|---|---|---|---|---|---|---|---|
DOK7 | ENST00000340083.6 | c.1171G>A | p.Gly391Arg | missense_variant | 7/7 | 1 | NM_173660.5 | ENSP00000344432 | P1 | |
DOK7 | ENST00000643608.1 | c.739G>A | p.Gly247Arg | missense_variant | 5/8 | ENSP00000495701 | ||||
DOK7 | ENST00000515886.5 | c.241G>A | p.Gly81Arg | missense_variant | 4/4 | 2 | ENSP00000492194 | |||
DOK7 | ENST00000507039.5 | c.*392G>A | 3_prime_UTR_variant | 7/7 | 2 | ENSP00000423614 |
Frequencies
GnomAD3 genomes AF: 0.000736 AC: 112AN: 152198Hom.: 1 Cov.: 34
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GnomAD3 exomes AF: 0.000847 AC: 193AN: 227988Hom.: 0 AF XY: 0.000880 AC XY: 110AN XY: 124986
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GnomAD4 exome AF: 0.00107 AC: 1557AN: 1453386Hom.: 1 Cov.: 114 AF XY: 0.00102 AC XY: 738AN XY: 722634
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GnomAD4 genome AF: 0.000735 AC: 112AN: 152316Hom.: 1 Cov.: 34 AF XY: 0.000631 AC XY: 47AN XY: 74486
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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 submitter | clinical testing | GeneDx | Jun 28, 2022 | In 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 submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 30, 2023 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 14, 2022 | The 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 submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 01, 2017 | - - |
Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.
MutationTaster
Benign
N;N;N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.
REVEL
Benign
Sift
Benign
D;.;.
Sift4G
Uncertain
D;.;.
Polyphen
P;.;.
Vest4
MutPred
Gain of solvent accessibility (P = 0.0014);.;.;
MVP
MPC
ClinPred
T
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at