Genetic Variant ENST00000316562.9:c.276G>T (chr20-3889376-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The ENST00000316562.9(PANK2):c.276G>T(p.Arg92Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. R92W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PANK2
ENST00000316562.9 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.33

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 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 2 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=0.33529252).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PANK2	NM_001386393.1 link	c.-55G>T		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.-55G>T		upstream_gene_variant		1	NM_001386393.1	ENSP00000477429.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

179352

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1423186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

704952

African (AFR)

AF:

0.00

AC:

AN:

32686

American (AMR)

AF:

0.00

AC:

AN:

37958

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25408

East Asian (EAS)

AF:

0.00

AC:

AN:

37494

South Asian (SAS)

AF:

0.00

AC:

AN:

81812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094010

Other (OTH)

AF:

0.00

AC:

AN:

58940

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000169

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.098

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.43

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.34

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

0.0

PhyloP100

1.3

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.22

REVEL

Uncertain

0.45

Sift

Uncertain

0.017

Sift4G

Uncertain

0.016

Vest4

0.33

ClinPred

0.74

GERP RS

3.9

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.12

gMVP

0.31

Mutation Taster

=82/18

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