rs587784367
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_007254.4(PNKP):c.302C>T(p.Pro101Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461836Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727216
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Microcephaly, seizures, and developmental delay Pathogenic:1Uncertain:1
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This variant has been identified compound heterozygous with the variant NM_007254.3:c.498G>A, r.199_498del, p.Leu67_Lys166del in two fetuses with microcephaly, aplasia/hypoplasia of the cerebrum and cerebellum (hypoplastic frontal lobes, no corpus callosum) and facial dysmorphism (retrognathia, hypertelorism, long philtrum). The variant is maternally inherited. This missense variant c.302C>T, p.(Pro101Leu) in exon 4 of PNKP has been reported in ClinVar (ID 159793). The variant is absent from the general population (gnomAD). Multiple in silico-tools predict this variant as damaging. The variant is located in the FHA-domain. Taken together, we classify this variant as likely pathogenic based on the ACMG recommendations (Richards et al., 2015, PMID 25741868; criteria: PS4_MOD;PM1_SUP;PM2_SUP;PM3;PP3). -
not provided Uncertain:2
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Inborn genetic diseases Uncertain:1
The p.P101L variant (also known as c.302C>T), located in coding exon 3 of the PNKP gene, results from a C to T substitution at nucleotide position 302. The proline at codon 101 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at