rs137852959

Positions:

• chr20-3918695-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_001386393.1(PANK2):​c.1231G>A​(p.Gly411Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: PANK2 NM_001386393.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 9.97

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001386393.1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 20-3918695-G-A is Pathogenic according to our data. Variant chr20-3918695-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-3918695-G-A is described in Lovd as [Likely_pathogenic]. Variant chr20-3918695-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PANK2	NM_001386393.1	c.1231G>A	p.Gly411Arg	missense_variant	6/7	ENST00000610179.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PANK2	ENST00000610179.7	c.1231G>A	p.Gly411Arg	missense_variant	6/7	1	NM_001386393.1	P2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000875 AC: 22 AN: 251484 Hom.: 0 AF XY: 0.0000809 AC XY: 11 AN XY: 135920

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000248 AC: 362 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.000246 AC XY: 179 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000308

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74330

Gnomad4 AFR AF: 0.0000724

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: 0.000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000348 Hom.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pigmentary pallidal degeneration Pathogenic:7 Other:1

not provided, no classification provided	literature only	GeneReviews	-	The most frequent PANK2 pathogenic variant, p.Gly521Arg, leads to a protein that is misfolded and devoid of activity [Zhang et al 2006]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 07, 2023	Variant summary: PANK2 c.1561G>A (p.Gly521Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 251484 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PANK2 causing Pantothenate Kinase-Associated Neurodegeneration (8.7e-05 vs 0.0011), allowing no conclusion about variant significance. c.1561G>A has been reported in the literature in multiple bi-allelic individuals affected with Pantothenate Kinase-Associated Neurodegeneration/Hallervorden-Spatz syndrome (example: Zhou_2001). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 11479594). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 521 of the PANK2 protein (p.Gly521Arg). This variant is present in population databases (rs137852959, gnomAD 0.02%). This missense change has been observed in individuals with atypical and typical pantothenate kinase-associated neurodegeneration (PMID: 11479594, 16450344, 22221393, 26795593). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4548). 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 have shown that this missense change affects PANK2 function (PMID: 15659606, 16272150). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 18, 2022	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Pathogenic, for Neurodegeneration with brain iron accumulation 1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation. (PMID:11479594,15834858,24075960) (PMID:12510040). PS3 => Well-established functional studies show a deleterious effect (PMID:16272150,15659606). -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PANK2 p.Gly521Arg variant in homozygosity consistently presents as classic PKAN in the literature (Li_2013_22416811, Wu_2013_23968566, Zhang_2006_16272150). The variant was identified in dbSNP (ID: rs137852959) “with Pathogenic allele”, ClinVar classified as pathogenic (submitters: Ambry Genetics, Center for Pediatric Genomic Medicine (Children's Mercy Hospital and Clinics), GeneDx, OMIM, Undiagnosed Diseases Program Translational Research Laboratory (NIH) and Groupe Hospitalier Pitie Salpetriere (Paris)), and in control databases in 35 of 277234 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 2 of 6468 chromosomes (freq: 0.0003), Latino in 3 of 34420 chromosomes (freq: 0.00009), European Non-Finnish in 28 of 126718 chromosomes (freq: 0.0002), African in 1 of 24030 chromosomes (freq: 0.00004), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), while not observed in the Ashkenazi Jewish, East Asian and European Finnish populations. The p.Gly521 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Arg to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	Jan 06, 2017	neurodegenerative syndrome; cerebellar ataxia; epilepsy; tremor -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 02, 2021	PS3, PS4, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 03, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2022	Functional studies show G521R leads to loss of protein catalytic activity (Zhang et al., 2006); This variant is associated with the following publications: (PMID: 25131622, 22221393, 11479594, 24215330, 22416811, 26828213, 26795593, 23968566, 29590070, 28708303, 16450344, 31628766, 30363918, 32654475, 33144682, 33098801, 31589614, 28252636, 16272150) -

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	research	Center for Precision Medicine, Vanderbilt University Medical Center	Mar 16, 2018	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2021

The c.1561G>A (p.G521R) alteration is located in coding exon 6 of the PANK2 gene. This alteration results from a G to A substitution at nucleotide position 1561, causing the glycine (G) at amino acid position 521 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (36/282886) total alleles studied, with a frequency of 0.02% (28/129190) in the European (non-Finnish) subpopulation. This alteration has been reported previously in the homozygous and compound heterozygous state in multiple individuals with pantothenate kinase-associated neurodegeneration (Zhou, 2001; Leoni, 2012; Wu, 2013; Chérot, 2018; Santambrogio, 2020). This amino acid position is highly conserved in available vertebrate species. Functional analyses in HEK293 cells demonstrated that the p.G521R alteration causes marked instability of the intermediate PANK2, and reduced production of the mature protein. In vitro enzymatic activity assay of mutant and wild type proteins revealed that p.G521R results in more than 90% reduction in enzyme activity compared to wild-type (Kotzbauer, 2005). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Pigmentary pallidal degeneration;C1846582:Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 20, 2022

- -

Retinitis pigmentosa Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DBGen Ocular Genomics

Jun 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.8	D;.;D;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;.;D;.;.
Vest4		0.99
MutPred		0.98		.;.;Gain of MoRF binding (P = 0.0165);.;.;
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: -24

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

Publications

LitVar

Other links and lift over

dbSNP: rs137852959; hg19: chr20-3899342;