Genetic Variant PANK2:p.Leu27Val (chr20-3889179-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The ENST00000316562.9(PANK2):c.79C>G(p.Leu27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L27I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PANK2
ENST00000316562.9 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.428

Publications

0 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 links:

PANK2-AS1 (HGNC:40732): (PANK2 antisense RNA 1)

PANK2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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: -1.1034 (below the threshold of 3.09). GenCC associations: The gene is linked to pantothenate kinase-associated neurodegeneration.

BP4

Computational evidence support a benign effect (MetaRNN=0.089555174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PANK2	NM_001386393.1 link	c.-252C>G		upstream_gene_variant		ENST00000610179.7	NP_001373322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PANK2	ENST00000610179.7 link	c.-252C>G		upstream_gene_variant		1	NM_001386393.1	ENSP00000477429.2		Q9BZ23-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457378

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33410

American (AMR)

AF:

0.00

AC:

AN:

44270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25938

East Asian (EAS)

AF:

0.00

AC:

AN:

39548

South Asian (SAS)

AF:

0.00

AC:

AN:

84984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110174

Other (OTH)

AF:

0.00

AC:

AN:

60216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

8.7

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.23

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.94

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.36

M_CAP

Benign

0.047

MetaRNN

Benign

0.090

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

0.0

PhyloP100

0.43

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.18

REVEL

Benign

0.18

Sift

Uncertain

0.0060

Sift4G

Benign

0.087

Polyphen

0.015

Vest4

0.26

MutPred

0.31

Gain of sheet (P = 0.0043);

MVP

0.77

MPC

0.46

ClinPred

0.15

GERP RS

-0.24

PromoterAI

-0.088

Neutral

(source)

Varity_R

0.10

gMVP

0.021

Mutation Taster

=92/8

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over