NM_173660.5:c.1306G>A
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_173660.5(DOK7):c.1306G>A(p.Gly436Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000566 in 1,608,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. G436R) has been classified as Uncertain significance.
Frequency
Consequence
NM_173660.5 missense
Scores
Clinical Significance
Conservation
Publications
- congenital myasthenic syndrome 10Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
- fetal akinesia deformation sequence 3Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- fetal akinesia deformation sequence 1Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- postsynaptic congenital myasthenic syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DOK7 | ENST00000340083.6 | c.1306G>A | p.Gly436Ser | missense_variant | Exon 7 of 7 | 1 | NM_173660.5 | ENSP00000344432.5 | ||
DOK7 | ENST00000643608.1 | c.874G>A | p.Gly292Ser | missense_variant | Exon 5 of 8 | ENSP00000495701.1 | ||||
DOK7 | ENST00000515886.5 | c.376G>A | p.Gly126Ser | missense_variant | Exon 4 of 4 | 2 | ENSP00000492194.1 | |||
DOK7 | ENST00000507039.5 | c.*527G>A | 3_prime_UTR_variant | Exon 7 of 7 | 2 | ENSP00000423614.1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152228Hom.: 0 Cov.: 34 show subpopulations
GnomAD2 exomes AF: 0.0000352 AC: 8AN: 227310 AF XY: 0.0000399 show subpopulations
GnomAD4 exome AF: 0.0000549 AC: 80AN: 1456166Hom.: 0 Cov.: 97 AF XY: 0.0000566 AC XY: 41AN XY: 723946 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152228Hom.: 0 Cov.: 34 AF XY: 0.0000807 AC XY: 6AN XY: 74358 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.1306G>A (p.G436S) 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 1306, causing the glycine (G) at amino acid position 436 to be replaced by a serine (S). 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
This sequence change replaces glycine with serine at codon 436 of the DOK7 protein (p.Gly436Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs201392182, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with DOK7-related conditions. ClinVar contains an entry for this variant (Variation ID: 283171). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
not provided Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at