rs1555788619

Variant names:

• chr20-3912471-A-ACT
• rs1555788619
• NM_001386393.1:c.920_921dupCT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001386393.1(PANK2):​c.920_921dupCT​(p.Phe308LeufsTer33) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PANK2 NM_001386393.1 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.83
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-3912471-A-ACT is Pathogenic according to our data. Variant chr20-3912471-A-ACT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 526628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386393.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PANK2	NM_001386393.1	MANE Select	c.920_921dupCT	p.Phe308LeufsTer33	frameshift	Exon 4 of 7	NP_001373322.1	Q9BZ23-4
	PANK2	NM_153638.4		c.1250_1251dupCT	p.Phe418LeufsTer33	frameshift	Exon 4 of 7	NP_705902.2	Q9BZ23-1
	PANK2	NM_001324191.2		c.377_378dupCT	p.Phe127LeufsTer33	frameshift	Exon 5 of 8	NP_001311120.1	Q9BZ23-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PANK2	ENST00000610179.7	TSL:1 MANE Select	c.920_921dupCT	p.Phe308LeufsTer33	frameshift	Exon 4 of 7	ENSP00000477429.2	Q9BZ23-4
	PANK2	ENST00000316562.9	TSL:1	c.1250_1251dupCT	p.Phe418LeufsTer33	frameshift	Exon 4 of 7	ENSP00000313377.4	Q9BZ23-1
	PANK2	ENST00000621507.1	TSL:1	c.377_378dupCT	p.Phe127LeufsTer33	frameshift	Exon 4 of 7	ENSP00000481523.1	Q9BZ23-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Pigmentary pallidal degeneration (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555788619; hg19: chr20-3893118;