rs372148913
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_007254.4(PNKP):c.968C>T(p.Thr323Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000827 in 1,583,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_007254.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000500 AC: 10AN: 200044Hom.: 0 AF XY: 0.0000464 AC XY: 5AN XY: 107794
GnomAD4 exome AF: 0.0000874 AC: 125AN: 1430980Hom.: 0 Cov.: 36 AF XY: 0.0000776 AC XY: 55AN XY: 708942
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74330
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Observed multiple times with a second PNKP variant in unrelated patients with features of a PNKP-related disorder referred for genetic testing at GeneDx and in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 35354845, 37916443, 32980744); Published functional studies demonstrate a damaging effect and show that this variant causes a significant loss of both 5'-kinase and 3'-phosphatase activity, increases radiation sensitivity, and impairs double strand DNA repair in vitro (PMID: 35354845); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22508754, 35354845, 37916443, 29655203, 34697416, 34040816, 32980744) -
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Inborn genetic diseases Pathogenic:1
The p.T323M variant (also known as c.968C>T), located in coding exon 10 of the PNKP gene, results from a C to T substitution at nucleotide position 968. The threonine at codon 323 is replaced by methionine, an amino acid with similar properties. This variant has been identified homozygous and in conjunction with other PNKP variants in individuals with seizures, microcephaly, global developmental delay, dyskinesia, abnormal MRI, lissencephaly, and/or polymicrogyria, and other clinical features consistent with PNKP-related neurodevelopmental disorder; in at least one instance, the variants were identified in trans (Lindy AS et al. Epilepsia, 2018 May;59:1062-1071; Garrelfs MR et al. Pediatr Neurol, 2020 Dec;113:26-3; Marcilla Vázquez C et al. J Pediatr Genet, 2021 Jun;10:164-172; Jiang B et al. Sci Rep, 2022 Mar;12:5386; Thuresson AC et al. Mol Genet Genomic Med, 2024 Jan;12:e2295; External communication, 2024). In multiple assays testing PNKP function, this variant showed functionally abnormal results (Jiang B et al. Sci Rep, 2022 Mar;12:5386). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Microcephaly, seizures, and developmental delay Pathogenic:1
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Ataxia - oculomotor apraxia type 4 Pathogenic:1
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Developmental and epileptic encephalopathy, 12 Pathogenic:1
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 323 of the PNKP protein (p.Thr323Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of PNKP-related conditions (PMID: 29655203, 32980744, 34040816, 35354845; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 159803). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PNKP protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PNKP function (PMID: 35354845). For these reasons, this variant has been classified as Pathogenic. -
PNKP-related disorder Uncertain:1
The PNKP c.968C>T variant is predicted to result in the amino acid substitution p.Thr323Met. This variant has been reported in the homozygous state, in combination with an additional variant (phase not provided), or with no zygosity provided, in individuals with microcephaly, seizures, and developmental delay (Marcilla Vázquez C et al 2020. PubMed ID: 34040816; Jiang B et al 2022. PubMed ID: 35354845; Lindy et al 2018. PubMed ID: 29655203 Supplemental Table 4; Garrelfs et al. 2020. PubMed ID: 32980744). In vitro studies using an overexpression system suggested that this variant may reduce protein function by multiple mechanisms (Jiang B et al 2022. PubMed ID: 35354845). This variant is reported in 0.0092% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at