rs137852967
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong
The NM_001386393.1(PANK2):c.1253C>T(p.Thr418Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,614,074 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T418R) has been classified as Uncertain significance.
Frequency
Consequence
NM_001386393.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PANK2 | NM_001386393.1 | c.1253C>T | p.Thr418Met | missense_variant | 6/7 | ENST00000610179.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PANK2 | ENST00000610179.7 | c.1253C>T | p.Thr418Met | missense_variant | 6/7 | 1 | NM_001386393.1 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152202Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251482Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135916
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 727234
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
Pigmentary pallidal degeneration Pathogenic:6Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Genetic Diagnostic of Neurological Diseases, University of Belgrade, School of Medicine | Jul 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 07, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 528 of the PANK2 protein (p.Thr528Met). This variant is present in population databases (rs137852967, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of Hallervorden-Spatz syndrome (HSS) and is associated with both classical and atypical HSS (PMID: 11479594, 15565311, 16437574, 23968566, 25802776, 26087139, 27185474, 28781879). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1283C>T, T418M. ClinVar contains an entry for this variant (Variation ID: 4556). 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 with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PANK2 function (PMID: 15659606, 16272150, 16437574). For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 02, 2003 | - - |
Pathogenic, no assertion criteria provided | research | Human Genetics Research Lab, Central University of Jammu | Jul 29, 2021 | The variant NM_153638.3(PANK2):c.1583C>T (p.Thr528Met) was found to be segregating with the disease in the family in autosomal recessive mode of inheritance. Two of the affected sibs were found homozygous for the variant whereas both healthy parents were found to be heterozygous for the variant. Source: OMIM 234200 Neurodegeneration with brain iron accumulation-1 (NBIA1), also known as Hallervorden-Spatz disease, is caused by homozygous or compound heterozygosity mutation in the pantothenate kinase-2 gene (PANK2; 606157) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Nov 14, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 12, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 28113101, 32705819, 30363918, 23968566, 27185474, 33098801, 34272103, 30838286, 12510040, 16437574, 32043823, 28781879, 25724846, 11479594, 35872528) - |
Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Feb 11, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP4,PP3,PP2,PP1. This variant was detected in homozygous state. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 06, 2022 | The c.1583C>T (p.T528M) alteration is located in exon 6 (coding exon 6) of the PANK2 gene. This alteration results from a C to T substitution at nucleotide position 1583, causing the threonine (T) at amino acid position 528 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of <0.01% (4/282880) total alleles studied. The highest observed frequency was <0.01% (1/25122) of European (Finnish) alleles. This alteration has been detected in the homozygous state and as compound heterozygous in trans with other pathogenic PANK2 alterations in numerous unrelated individuals with pantothenate kinase-associated neurodegeneration (Golanska, 2015; Wu, 2013; Hartig, 2006; Hayflick, 2003; Zhou, 2001). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at