NM_007254.4:c.1009G>C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_007254.4(PNKP):āc.1009G>Cā(p.Glu337Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,554,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E337E) has been classified as Likely benign.
Frequency
Consequence
NM_007254.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000593 AC: 9AN: 151874Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000249 AC: 4AN: 160814Hom.: 0 AF XY: 0.0000233 AC XY: 2AN XY: 85802
GnomAD4 exome AF: 0.0000121 AC: 17AN: 1402710Hom.: 0 Cov.: 37 AF XY: 0.0000116 AC XY: 8AN XY: 692370
GnomAD4 genome AF: 0.0000593 AC: 9AN: 151874Hom.: 0 Cov.: 32 AF XY: 0.0000809 AC XY: 6AN XY: 74180
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The p.E337Q variant (also known as c.1009G>C), located in coding exon 10 of the PNKP gene, results from a G to C substitution at nucleotide position 1009. The glutamic acid at codon 337 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a subject with juvenile myoclonic epilepsy (Lee CG et al. PLoS ONE, 2018 Jun;13:e0199321). This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Charcot-Marie-Tooth disease type 2B2;C3150667:Microcephaly, seizures, and developmental delay;C4225397:Ataxia - oculomotor apraxia type 4 Uncertain:1
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Developmental and epileptic encephalopathy, 12 Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 337 of the PNKP protein (p.Glu337Gln). This variant is present in population databases (rs780121125, gnomAD 0.008%). This missense change has been observed in individual(s) with juvenile myoclonic epilepsy (PMID: 29924869). ClinVar contains an entry for this variant (Variation ID: 391407). 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 glutamine 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 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at