rs1555789557

chr20-3916939-GATGA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001386393.1(PANK2):c.1096_1099del(p.Met366AlafsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PANK2 NM_001386393.1 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.94

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 20-3916939-GATGA-G is Pathogenic according to our data. Variant chr20-3916939-GATGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 417619.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PANK2	NM_001386393.1	c.1096_1099del	p.Met366AlafsTer18	frameshift_variant	5/7	ENST00000610179.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PANK2	ENST00000610179.7	c.1096_1099del	p.Met366AlafsTer18	frameshift_variant	5/7	1	NM_001386393.1	P2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pigmentary pallidal degeneration Pathogenic:1

Pathogenic, no assertion criteria provided

research

Dr. Faghihi's Medical Genetic Center

Nov 05, 2016

An 8 years old Iranian girl was admitted to Namazi Hospital (Shiraz, Iran) in 2015 with clinical diagnosis of dystonia who was apparently normal before the age of 4. She developed bone fracture, muscle rigidity, abnormal movement, lack of coordination, chorea, and dystonia with seizure attacks. She was intellectually normal but she had speech problem due to medications she was taking which were Sirdalud (Tizanidine), Gabax, trihexidine and NA Valporate. Multiplanar multisequential MRI images through the brain with usual protocol were taken which demonstrated normal signal intensity of both cerebral hemispheres with no sign of mass or hemorrhage or ischemic infarction. No hydrocephalus or shift of midline structure was found. Posterior fossa structures including cerebral hemispheres showed normal signal intensity without any mass or hemorrhage or ischemic infarction. 7the-8the nerve root complexes appeared normal and pituitary gland was also normal with no sign of gross mass. No extra-axial mass or hematoma or fluid collection was observed. It is worth noting that generalized cortical atrophy was considerable which was more than that of expected for the patient's age. Mucosal thickening was noted at both ethmoidal maxillary sinuses due to sinusitis. Mild inflammatory change at right mastoid air cells and the "eye-of-the-tiger" sign in MRI imaging was remarkable. But, MRI of the cervical spine without contrast showed normal features. Paraclinical examinations were also requested which showed increased level of alkaline phosphatase (ALP) (191 U/L) and creatine phosphokinase (CPK) (456 U/L). -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1555789557; hg19: chr20-3897586;