20-3889381-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_153638.4(PANK2):c.281G>A(p.Arg94His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,422,704 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R94G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PANK2
NM_153638.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.391

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 3 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153638.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PANK2	NM_153638.4	c.281G>A	p.Arg94His	missense	Exon 1 of 7	NP_705902.2	Q9BZ23-1
PANK2	NM_001324192.1	c.281G>A	p.Arg94His	missense	Exon 1 of 2	NP_001311121.1
PANK2	NM_024960.6	c.-246+477G>A		intron	N/A	NP_079236.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PANK2	ENST00000316562.9	TSL:1	c.281G>A	p.Arg94His	missense	Exon 1 of 7	ENSP00000313377.4	Q9BZ23-1
PANK2	ENST00000497424.5	TSL:2	c.-246+477G>A		intron	N/A	ENSP00000417609.1	Q9BZ23-2
PANK2	ENST00000495692.5	TSL:3	c.-538+365G>A		intron	N/A	ENSP00000476745.1	V9GYH1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1422704

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

704666

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32698

American (AMR)

AF:

0.00

AC:

AN:

38032

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25408

East Asian (EAS)

AF:

0.00

AC:

AN:

37468

South Asian (SAS)

AF:

0.00

AC:

AN:

81786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1094058

Other (OTH)

AF:

0.00

AC:

AN:

58942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.047

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.52

M_CAP

Pathogenic

0.91

MetaRNN

Uncertain

0.57

MetaSVM

Uncertain

0.060

MutationAssessor

Benign

0.0

PhyloP100

0.39

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.34

REVEL

Uncertain

0.33

Sift

Uncertain

0.0040

Sift4G

Benign

0.062

Polyphen

0.82

Vest4

0.44

MutPred

0.36

Loss of methylation at R94 (P = 0.0263)

MVP

0.99

MPC

0.59

ClinPred

0.44

GERP RS

2.8

PromoterAI

-0.10

Neutral

(source)

Varity_R

0.14

gMVP

0.21

Mutation Taster

=95/5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over