NM_001386393.1:c.47G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001386393.1(PANK2):c.47G>C(p.Gly16Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.872 in 1,523,714 control chromosomes in the GnomAD database, including 580,652 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G16R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.90 ( 61838 hom., cov: 36)

Exomes 𝑓: 0.87 ( 518814 hom. )

Consequence

PANK2
NM_001386393.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.760

Publications

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

PANK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=1.164075E-6).

BP6

Variant 20-3889477-G-C is Benign according to our data. Variant chr20-3889477-G-C is described in ClinVar as Benign. ClinVar VariationId is 96526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PANK2	NM_001386393.1 link	c.47G>C	p.Gly16Ala	missense_variant	Exon 1 of 7	ENST00000610179.7	NP_001373322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PANK2	ENST00000610179.7 link	c.47G>C	p.Gly16Ala	missense_variant	Exon 1 of 7	1	NM_001386393.1	ENSP00000477429.2		Q9BZ23-4

Frequencies

GnomAD3 genomes

AF:

0.899

AC:

136790

AN:

152152

Hom.:

61777

Cov.:

show subpopulations

Gnomad AFR

AF:

0.978

Gnomad AMI

AF:

0.869

Gnomad AMR

AF:

0.932

Gnomad ASJ

AF:

0.788

Gnomad EAS

AF:

0.789

Gnomad SAS

AF:

0.772

Gnomad FIN

AF:

0.880

Gnomad MID

AF:

0.867

Gnomad NFE

AF:

0.869

Gnomad OTH

AF:

0.914

GnomAD2 exomes

AF:

0.862

AC:

110757

AN:

128528

AF XY:

0.853

show subpopulations

Gnomad AFR exome

AF:

0.983

Gnomad AMR exome

AF:

0.932

Gnomad ASJ exome

AF:

0.780

Gnomad EAS exome

AF:

0.803

Gnomad FIN exome

AF:

0.870

Gnomad NFE exome

AF:

0.875

Gnomad OTH exome

AF:

0.858

GnomAD4 exome

AF:

0.869

AC:

1191574

AN:

1371446

Hom.:

518814

Cov.:

AF XY:

0.865

AC XY:

585057

AN XY:

676422

show subpopulations

African (AFR)

AF:

0.982

AC:

30339

AN:

30908

American (AMR)

AF:

0.931

AC:

30816

AN:

33096

Ashkenazi Jewish (ASJ)

AF:

0.786

AC:

18210

AN:

23160

East Asian (EAS)

AF:

0.787

AC:

28459

AN:

36162

South Asian (SAS)

AF:

0.764

AC:

58362

AN:

76406

European-Finnish (FIN)

AF:

0.873

AC:

29272

AN:

33542

Middle Eastern (MID)

AF:

0.832

AC:

4473

AN:

5376

European-Non Finnish (NFE)

AF:

0.876

AC:

942292

AN:

1075698

Other (OTH)

AF:

0.864

AC:

49351

AN:

57098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

10005

20011

30016

40022

50027

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20972

41944

62916

83888

104860

<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:

0.899

AC:

136909

AN:

152268

Hom.:

61838

Cov.:

AF XY:

0.898

AC XY:

66859

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.978

AC:

40671

AN:

41574

American (AMR)

AF:

0.932

AC:

14275

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.788

AC:

2736

AN:

3472

East Asian (EAS)

AF:

0.790

AC:

4071

AN:

5156

South Asian (SAS)

AF:

0.773

AC:

3735

AN:

4830

European-Finnish (FIN)

AF:

0.880

AC:

9334

AN:

10612

Middle Eastern (MID)

AF:

0.864

AC:

254

AN:

294

European-Non Finnish (NFE)

AF:

0.869

AC:

59117

AN:

67994

Other (OTH)

AF:

0.910

AC:

1925

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

729

1458

2187

2916

3645

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

900

1800

2700

3600

4500

<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:

0.839

Hom.:

5807

Bravo

AF:

0.911

TwinsUK

AF:

0.886

AC:

3285

ALSPAC

AF:

0.876

AC:

3378

ESP6500AA

AF:

0.983

AC:

3009

ESP6500EA

AF:

0.916

AC:

6120

ExAC

AF:

0.837

AC:

84645

Asia WGS

AF:

0.809

AC:

2811

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 92. Only high quality variants are reported. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 30, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 06, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Pigmentary pallidal degeneration

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.18

T;T

MetaRNN

Benign

0.0000012

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

N;.

PhyloP100

0.76

PrimateAI

Uncertain

0.76

PROVEAN

Benign

0.31

N;.

REVEL

Benign

0.27

Sift

Benign

1.0

T;.

Sift4G

Benign

0.77

T;T

Polyphen

0.0

B;.

Vest4

0.13

MPC

0.48

ClinPred

0.0065

GERP RS

4.7

PromoterAI

-0.019

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.15

Mutation Taster

=99/1

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over