rs141251138
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_007254.4(PNKP):c.498G>T(p.Lys166Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. 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. K166Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_007254.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PNKP | NM_007254.4 | c.498G>T | p.Lys166Asn | missense_variant, splice_region_variant | 4/17 | ENST00000322344.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PNKP | ENST00000322344.8 | c.498G>T | p.Lys166Asn | missense_variant, splice_region_variant | 4/17 | 1 | NM_007254.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 11, 2022 | ClinVar contains an entry for this variant (Variation ID: 1062350). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 166 of the PNKP protein (p.Lys166Asn). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.