rs137852967

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5PP3PP5_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 Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

PANK2
NM_001386393.1 missense

Scores

3
7
9

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 6.14
Variant links:
Genes affected
PANK2 (HGNC:15894): (pantothenate kinase 2) This gene encodes a protein belonging to the pantothenate kinase family and is the only member of that family to be expressed in mitochondria. Pantothenate kinase is a key regulatory enzyme in the biosynthesis of coenzyme A (CoA) in bacteria and mammalian cells. It catalyzes the first committed step in the universal biosynthetic pathway leading to CoA and is itself subject to regulation through feedback inhibition by acyl CoA species. Mutations in this gene are associated with HARP syndrome and pantothenate kinase-associated neurodegeneration (PKAN), formerly Hallervorden-Spatz syndrome. Alternative splicing, involving the use of alternate first exons, results in multiple transcripts encoding different isoforms. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr20-3918717-C-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.782
PP5
Variant 20-3918717-C-T is Pathogenic according to our data. Variant chr20-3918717-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-3918717-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PANK2NM_001386393.1 linkc.1253C>T p.Thr418Met missense_variant Exon 6 of 7 ENST00000610179.7 NP_001373322.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PANK2ENST00000610179.7 linkc.1253C>T p.Thr418Met missense_variant Exon 6 of 7 1 NM_001386393.1 ENSP00000477429.2 Q9BZ23-4

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152202
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251482
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000246
AC:
36
AN:
1461872
Hom.:
0
Cov.:
32
AF XY:
0.0000289
AC XY:
21
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000288
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152202
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000800
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pigmentary pallidal degeneration Pathogenic:6Other:1
Jul 01, 2020
Laboratory for Molecular Genetic Diagnostic of Neurological Diseases, University of Belgrade, School of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Nov 14, 2023
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 29, 2021
Human Genetics Research Lab, Central University of Jammu
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

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) -

Jun 07, 2019
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 02, 2003
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not provided Pathogenic:2
Jul 01, 2020
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 12, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
-
Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Feb 11, 2019
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jul 06, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

PANK2-related disorder Pathogenic:1
Apr 29, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The PANK2 c.1583C>T variant is predicted to result in the amino acid substitution p.Thr528Met. This variant was reported in individuals with Pantothenate kinase-associated neurodegeneration (Zhou et al. 2001. PubMed ID: 11479594; Wu et al. 2013. PubMed ID: 23968566; Yapici et al. 2016. PubMed ID: 27185474; Akcakaya et al. 2017. PubMed ID: 28113101). This variant is reported in 0.0040% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.19
CADD
Uncertain
25
DANN
Benign
0.97
DEOGEN2
Uncertain
0.76
.;.;D;.;.
Eigen
Benign
0.012
Eigen_PC
Benign
0.098
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.89
.;D;D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.78
D;D;D;D;D
MetaSVM
Uncertain
0.66
D
MutationAssessor
Benign
0.79
.;.;N;.;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-1.5
N;.;N;.;.
REVEL
Uncertain
0.60
Sift
Benign
0.20
T;.;T;.;.
Sift4G
Benign
0.21
T;T;T;T;T
Polyphen
0.85
.;.;P;.;.
Vest4
0.48
MutPred
0.76
.;.;Gain of MoRF binding (P = 0.0994);.;.;
MVP
0.97
MPC
0.71
ClinPred
0.55
D
GERP RS
3.2
Varity_R
0.22
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137852967; hg19: chr20-3899364; COSMIC: COSV57256401; COSMIC: COSV57256401; API