20-3918717-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T418R) has been classified as Likely pathogenic.

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:12O:1

Conservation

PhyloP100: 6.14

Publications

31 publications found

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 Gene-Disease associations (from GenCC):

pantothenate kinase-associated neurodegeneration
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

PANK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-3918717-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3233574.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 41 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.17856 (below the threshold of 3.09). Trascript score misZ: -0.052065 (below the threshold of 3.09). GenCC associations: The gene is linked to pantothenate kinase-associated neurodegeneration.

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/Likely_pathogenic. ClinVar VariationId is 4556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PANK2	NM_001386393.1 link	c.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
PANK2	ENST00000610179.7 link	c.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:

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

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251482

AF XY:

0.0000221

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 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

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1111994

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000959

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

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

Jan 02, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

- -

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. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jun 07, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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) -

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

- -

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

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.76

.;.;D;.;.

Eigen

Benign

0.012

Eigen_PC

Benign

0.098

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

.;D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.78

D;D;D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

0.79

.;.;N;.;.

PhyloP100

6.1

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

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over