chr20-3889483-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1

The NM_001386393.1(PANK2):c.53G>A(p.Arg18Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,488,860 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R18G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000070 ( 1 hom. )

Consequence

PANK2
NM_001386393.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.04

Publications

5 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 -8 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=0.009393901).

BP6

Variant 20-3889483-G-A is Benign according to our data. Variant chr20-3889483-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 526630.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000164 (25/152296) while in subpopulation EAS AF = 0.00445 (23/5168). AF 95% confidence interval is 0.00304. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PANK2	NM_001386393.1 link	c.53G>A	p.Arg18Gln	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.53G>A	p.Arg18Gln	missense_variant	Exon 1 of 7	1	NM_001386393.1	ENSP00000477429.2		Q9BZ23-4

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00444

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000288

AC:

AN:

86722

AF XY:

0.000225

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000696

AC:

AN:

1336564

Hom.:

Cov.:

AF XY:

0.0000609

AC XY:

AN XY:

657274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27904

American (AMR)

AF:

0.00

AC:

AN:

26910

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21562

East Asian (EAS)

AF:

0.00221

AC:

AN:

34396

South Asian (SAS)

AF:

0.000125

AC:

AN:

71970

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5174

European-Non Finnish (NFE)

AF:

0.00000283

AC:

AN:

1060790

Other (OTH)

AF:

0.0000899

AC:

AN:

55648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

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

AF:

0.000164

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41578

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00445

AC:

AN:

5168

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.000175

Hom.:

Bravo

AF:

0.000178

ExAC

AF:

0.000303

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pigmentary pallidal degeneration

Uncertain:1Benign:1

Mar 01, 2022

Department of Neurology, Xijing Hospital, Fourth Military Medical University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 12, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PANK2 c.383G>A (p.Arg128Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 86722 control chromosomes (gnomAD), predominantly at a frequency of 0.0033 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PANK2 causing Pantothenate Kinase-Associated Neurodegeneration phenotype (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.383G>A has been reported in the literature in individuals affected with Pantothenate Kinase-Associated Neurodegeneration (Chang_2020). The variant was also found co-occurring with another pathogenic variant in an individual with retinitis pigmentosa (CNGA1 c.179del, p.Gly60fs, Katagiri_2014), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

0.0079

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0094

T;T

MetaSVM

Uncertain

-0.0074

MutationAssessor

Benign

0.0

N;.

PhyloP100

3.0

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.010

N;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.027

D;.

Sift4G

Benign

0.41

T;T

Polyphen

0.91

P;.

Vest4

0.28

MutPred

0.33

Loss of methylation at R128 (P = 0.0011);.;

MVP

0.97

MPC

0.53

ClinPred

0.23

GERP RS

3.8

PromoterAI

0.014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.34

Mutation Taster

=91/9

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over