rs775762473
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_007254.4(PNKP):āc.1381A>Gā(p.Asn461Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000385 in 1,556,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N461H) has been classified as Uncertain significance.
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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PNKP | NM_007254.4 | c.1381A>G | p.Asn461Asp | missense_variant | 15/17 | ENST00000322344.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PNKP | ENST00000322344.8 | c.1381A>G | p.Asn461Asp | missense_variant | 15/17 | 1 | NM_007254.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000264 AC: 4AN: 151576Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000187 AC: 3AN: 160074Hom.: 0 AF XY: 0.0000348 AC XY: 3AN XY: 86314
GnomAD4 exome AF: 0.0000398 AC: 56AN: 1405404Hom.: 0 Cov.: 38 AF XY: 0.0000331 AC XY: 23AN XY: 694100
GnomAD4 genome ? AF: 0.0000264 AC: 4AN: 151576Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74012
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 15, 2023 | The c.1381A>G (p.N461D) alteration is located in exon 15 (coding exon 14) of the PNKP gene. This alteration results from a A to G substitution at nucleotide position 1381, causing the asparagine (N) at amino acid position 461 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 20, 2017 | A variant of uncertain significance has been identified in the PNKP gene. The N461D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N461D variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N461D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Microcephaly, seizures, and developmental delay;C4225397:Ataxia - oculomotor apraxia type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Developmental and epileptic encephalopathy, 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2022 | This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 461 of the PNKP protein (p.Asn461Asp). This variant is present in population databases (rs775762473, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. ClinVar contains an entry for this variant (Variation ID: 409614). 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 not expected to disrupt PNKP protein function. 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