20-3889134-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The ENST00000316562.9(PANK2):c.34C>T(p.His12Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000723 in 1,562,132 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 1 hom. )

Consequence

PANK2
ENST00000316562.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.301

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03422314).

BP6

Variant 20-3889134-C-T is Benign according to our data. Variant chr20-3889134-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 935319.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons
PANK2-AS1	XR_001754478.3 linkuse as main transcript	n.40G>A		non_coding_transcript_exon_variant	1/2
PANK2	NM_153638.4 linkuse as main transcript	c.34C>T	p.His12Tyr	missense_variant	1/7
PANK2	NM_001324192.1 linkuse as main transcript	c.34C>T	p.His12Tyr	missense_variant	1/2
PANK2	NM_024960.6 linkuse as main transcript	c.-246+230C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Appris	UniProt
PANK2	ENST00000316562.9 linkuse as main transcript	c.34C>T	p.His12Tyr	missense_variant	1/7	1	A2	Q9BZ23-1
PANK2-AS1	ENST00000702266.1 linkuse as main transcript	n.40G>A		non_coding_transcript_exon_variant	1/1
PANK2	ENST00000495692.5 linkuse as main transcript	c.-538+118C>T		intron_variant		3
PANK2	ENST00000497424.5 linkuse as main transcript	c.-246+230C>T		intron_variant		2		Q9BZ23-2

Frequencies

GnomAD3 genomes

AF:

0.000374

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000703

AC:

AN:

170798

Hom.:

AF XY:

0.0000328

AC XY:

AN XY:

91350

show subpopulations

Gnomad AFR exome

AF:

0.00110

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000146

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1409800

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

696472

show subpopulations

Gnomad4 AFR exome

AF:

0.00146

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000461

Gnomad4 OTH exome

AF:

0.0000857

GnomAD4 genome

AF:

0.000368

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000296

Hom.:

Bravo

AF:

0.000423

ESP6500AA

AF:

0.000919

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000504

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 08, 2024

Variant summary: PANK2 c.34C>T (p.His12Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7e-05 in 170798 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PANK2 causing Pantothenate Kinase-Associated Neurodegeneration (7e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.34C>T in individuals affected with Pantothenate Kinase-Associated Neurodegeneration and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 935319). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2023

The c.34C>T (p.H12Y) alteration is located in exon 1 (coding exon 1) of the PANK2 gene. This alteration results from a C to T substitution at nucleotide position 34, causing the histidine (H) at amino acid position 12 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Pigmentary pallidal degeneration

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.11

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.59

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.39

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.034

MetaSVM

Uncertain

0.094

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.49

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.051

Polyphen

0.0

Vest4

0.21

MVP

0.85

MPC

0.59

ClinPred

0.23

GERP RS

3.6

Varity_R

0.30

gMVP

0.040

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over