dbSNP rs137852959: PANK2:p.Gly411Arg (chr20-3918695-G-A) – ACMG Classification: Pathogenic (19 pts)

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3PM1PP2PP3_StrongPP5_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. 14/24 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000803577: "Well-established functional studies show a deleterious effect" (PMID:16272150,15659606)" and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

PANK2
NM_001386393.1 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 9.97

Publications

53 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

PANK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000803577: "Well-established functional studies show a deleterious effect" (PMID:16272150,15659606); SCV000830927: Experimental studies have shown that this missense change affects PANK2 function (PMID: 15659606, 16272150).; SCV000244256: 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).; SCV000616816: Functional studies show G521R leads to loss of protein catalytic activity (Zhang et al., 2006)

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001386393.1

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, 0.958

PP5

Variant 20-3918695-G-A is Pathogenic according to our data. Variant chr20-3918695-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386393.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PANK2	NM_001386393.1	MANE Select	c.1231G>A	p.Gly411Arg	missense	Exon 6 of 7	NP_001373322.1	Q9BZ23-4
PANK2	NM_153638.4		c.1561G>A	p.Gly521Arg	missense	Exon 6 of 7	NP_705902.2	Q9BZ23-1
PANK2	NM_001324191.2		c.688G>A	p.Gly230Arg	missense	Exon 7 of 8	NP_001311120.1	Q9BZ23-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PANK2	ENST00000610179.7	TSL:1 MANE Select	c.1231G>A	p.Gly411Arg	missense	Exon 6 of 7	ENSP00000477429.2	Q9BZ23-4
PANK2	ENST00000316562.9	TSL:1	c.1561G>A	p.Gly521Arg	missense	Exon 6 of 7	ENSP00000313377.4	Q9BZ23-1
PANK2	ENST00000621507.1	TSL:1	c.688G>A	p.Gly230Arg	missense	Exon 6 of 7	ENSP00000481523.1	Q9BZ23-2

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000875

AC:

AN:

251484

AF XY:

0.0000809

show subpopulations

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 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.:

Cov.:

AF XY:

0.000246

AC XY:

179

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

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:

0.000308

AC:

343

AN:

1112008

Other (OTH)

AF:

0.0000993

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000217

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.000387

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pigmentary pallidal degeneration (11)

not provided (5)

Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (2)

Inborn genetic diseases (1)

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

Retinitis pigmentosa (1)

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.0

PhyloP100

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.8

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.98

Gain of MoRF binding (P = 0.0165)

MVP

1.0

MPC

1.5

ClinPred

1.0

GERP RS

5.1

Varity_R

0.97

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over