rs41279408

chr20-3923290-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001386393.1(PANK2):c.1379C>T(p.Pro460Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P460P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: PANK2 NM_001386393.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 1.35

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18198228).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PANK2	NM_001386393.1	c.1379C>T	p.Pro460Leu	missense_variant	7/7	ENST00000610179.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PANK2	ENST00000610179.7	c.1379C>T	p.Pro460Leu	missense_variant	7/7	1	NM_001386393.1	P2
	ENST00000619343.1	n.78+33G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251484 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000146 AC: 214 AN: 1461876 Hom.: 0 Cov.: 30 AF XY: 0.000150 AC XY: 109 AN XY: 727244

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74432

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000125 Hom.: 0

Bravo AF: 0.0000642

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2023	Reported previously in a patient with tremors in the lower extremities, balance difficulties, shuffling gait, and abnormal brain MRI, who also harbored a second variant (phase unknown) (Lee et al., 2020); Reported previously, using alternate nomenclature, on one allele in a patient with atypical Hallervorden-Spatz syndrome; however, no further clinical or segregation information was provided (Hayflick et al., 2003); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 12510040, 31540697, 20629144, 33072517) -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Pigmentary pallidal degeneration Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 05, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 570 of the PANK2 protein (p.Pro570Leu). This variant is present in population databases (rs41279408, gnomAD 0.05%). This missense change has been observed in individual(s) with PANK2-related conditions (PMID: 12510040, 20629144, 33072517). This variant is also known as c.1379C>T (p.Pro460Leu). ClinVar contains an entry for this variant (Variation ID: 570102). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.12	N;N;.;.
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.48
MVP		0.95
MPC		0.74
ClinPred		0.13	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.48

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

Other links and lift over

dbSNP: rs41279408; hg19: chr20-3903937;