20-3889136-TTGGGCGGCGCCGCCATCACTCTCTTC-T

Position:

chr20-3889136-TTGGGCGGCGCCGCCATCACTCTCTTC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5

The ENST00000316562.9(PANK2):c.42_67del(p.Ala15ThrfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000048 in 1,563,938 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

PANK2
ENST00000316562.9 frameshift

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 2.32

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_pathogenic. Variant got 9 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 126 pathogenic variants in the truncated region.

PP5

Variant 20-3889136-TTGGGCGGCGCCGCCATCACTCTCTTC-T is Pathogenic according to our data. Variant chr20-3889136-TTGGGCGGCGCCGCCATCACTCTCTTC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 422512.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein
PANK2-AS1	XR_001754478.3 linkuse as main transcript	n.12_37del		non_coding_transcript_exon_variant	1/2
PANK2	NM_001324192.1 linkuse as main transcript	c.42_67del	p.Ala15ThrfsTer24	frameshift_variant	1/2	NP_001311121.1
PANK2	NM_153638.4 linkuse as main transcript	c.42_67del	p.Ala15ThrfsTer24	frameshift_variant	1/7	NP_705902.2
PANK2	NM_024960.6 linkuse as main transcript	c.-246+238_-246+263del		intron_variant		NP_079236.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	Appris	UniProt
PANK2	ENST00000316562.9 linkuse as main transcript	c.42_67del	p.Ala15ThrfsTer24	frameshift_variant	1/7	1	ENSP00000313377	A2	Q9BZ23-1
PANK2-AS1	ENST00000702266.1 linkuse as main transcript	n.12_37del		non_coding_transcript_exon_variant	1/1
PANK2	ENST00000495692.5 linkuse as main transcript	c.-538+126_-538+151del		intron_variant		3	ENSP00000476745
PANK2	ENST00000497424.5 linkuse as main transcript	c.-246+238_-246+263del		intron_variant		2	ENSP00000417609		Q9BZ23-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000230

AC:

AN:

173688

Hom.:

AF XY:

0.0000215

AC XY:

AN XY:

92972

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000568

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000482

AC:

AN:

1411740

Hom.:

AF XY:

0.0000358

AC XY:

AN XY:

697604

show subpopulations

Gnomad4 AFR exome

AF:

0.0000311

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:

0.0000608

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000294

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.0000302

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pigmentary pallidal degeneration

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 23, 2022	This sequence change creates a premature translational stop signal (p.Ala15Thrfs*24) in the PANK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 556 amino acid(s) of the PANK2 protein. This variant is present in population databases (rs760822872, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with PANK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 422512). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 02, 2021	Variant summary: PANK2 c.42_67del26 (p.Ala15ThrfsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.3e-05 in 173688 control chromosomes (gnomAD). To our knowledge, no occurrence of c.42_67del26 in individuals affected with Pantothenate Kinase-Associated Neurodegeneration and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2016

The c.42_67del26 variant in the PANK2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.42_67del26 variant causes a frameshift starting with codon Alanine 15, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 24 of the new reading frame, denoted p.Ala15ThrfsX24. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.42_67del26 variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.42_67del26 as a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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