rs137852961
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_Very_Strong
The NM_001386393.1(PANK2):c.460C>T(p.Arg154Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,034 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R154Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001386393.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PANK2 | NM_001386393.1 | c.460C>T | p.Arg154Trp | missense_variant | 2/7 | ENST00000610179.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PANK2 | ENST00000610179.7 | c.460C>T | p.Arg154Trp | missense_variant | 2/7 | 1 | NM_001386393.1 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251420Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135870
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727246
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74312
ClinVar
Submissions by phenotype
Pigmentary pallidal degeneration Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 28, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 264 of the PANK2 protein (p.Arg264Trp). This variant is present in population databases (rs137852961, gnomAD 0.01%). This missense change has been observed in individuals with pantothenate kinase-associated neurodegeneration (PMID: 11479594, 16437574, 22221393). This variant is also known as p.R154W . ClinVar contains an entry for this variant (Variation ID: 4550). 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 PANK2 protein function. This variant disrupts the p.Arg264 amino acid residue in PANK2. Other variant(s) that disrupt this residue have been observed in individuals with PANK2-related conditions (PMID: 16437574, 33098801), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2001 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 27, 2022 | Observed multiple times with a second PANK2 variant in unrelated patients with PANK2-related neurodegeneration in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Darling et al., 2017; Hartig et al., 2006; Zhou et al., 2001); Published functional studies demonstrate that the variant results in a significant decrease in PANK2 protein activity (Hong et al., 2007; Zhang et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31540697, 27544236, 32928263, 28456385, 22221393, 11479594, 32456086, 16272150, 16437574, 28845923, 17631502) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at