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). Synonymous variant affecting the same amino acid position (i.e. T323T) has been classified as Likely benign.
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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PNKP | NM_007254.4 | c.968C>T | p.Thr323Met | missense_variant | 11/17 | ENST00000322344.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PNKP | ENST00000322344.8 | c.968C>T | p.Thr323Met | missense_variant | 11/17 | 1 | NM_007254.4 | P1 |
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 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 17, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 25, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 19, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in heterozygous state in a patient with epilepsy (Lindy et al., 2018); This variant is associated with the following publications: (PMID: 29655203) - |
Microcephaly, seizures, and developmental delay Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 05, 2013 | - - |
Ataxia - oculomotor apraxia type 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Hadassah Hebrew University Medical Center | - | - - |
Developmental and epileptic encephalopathy, 12 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | 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 individuals with clinical features of PNKP-related conditions (PMID: 29655203, 32980744, 34040816, 35354845; Invitae). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 09, 2022 | The c.968C>T (p.T323M) alteration is located in exon 11 (coding exon 10) of the PNKP gene. This alteration results from a C to T substitution at nucleotide position 968, causing the threonine (T) at amino acid position 323 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of <0.01% (10/200044) total alleles studied. The highest observed frequency was 0.02% (1/5142) of Other alleles. This alteration was reported in a 7 year old patient with microcephaly, seizures, developmental delay, ataxia, and polyneuropathy (Garrelfs, 2020). This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
PNKP-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 03, 2024 | 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