19-49865127-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_007254.4(PNKP):c.498G>A(p.Lys166Lys) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_007254.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000805 AC: 2AN: 248566Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 135008
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
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Microcephaly, seizures, and developmental delay Uncertain:1
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Developmental and epileptic encephalopathy, 12 Uncertain:1
This sequence change affects codon 166 of the PNKP mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PNKP protein. This variant also falls at the last nucleotide of exon 4 of the PNKP coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs141251138, ExAC 0.005%). This variant has not been reported in the literature in individuals with PNKP-related disease. ClinVar contains an entry for this variant (Variation ID: 211920). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at