rs137852967

Positions:

chr20-3918717-C-T

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

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

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

PANK2
NM_001386393.1 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O: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]

PANK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001386393.1

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/exons	MANE	UniProt
PANK2	NM_001386393.1 linkuse as main transcript	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 linkuse as main transcript	c.1253C>T	p.Thr418Met	missense_variant	6/7	1	NM_001386393.1	P2	Q9BZ23-4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

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:

AN:

251482

Hom.:

AF XY:

0.0000221

AC XY:

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:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

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:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

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.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Benign

0.97

Eigen

Benign

0.012

Eigen_PC

Benign

0.098

FATHMM_MKL

Uncertain

0.95

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.78

D;D;D;D;D

MetaSVM

Uncertain

0.66

MutationTaster

Benign

0.76

A;A

PrimateAI

Uncertain

0.73

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over