20-3889633-C-A

Variant names:

• chr20-3889633-C-A
• rs137852969
• NM_001386393.1:c.203C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001386393.1(PANK2):​c.203C>A​(p.Ser68*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,416,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S68S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PANK2 NM_001386393.1 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.0700
• Publications: 4 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 11 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 20-3889633-C-A is Pathogenic according to our data. Variant chr20-3889633-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4561.Status of the report is no_assertion_criteria_provided, 0 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.203C>A	p.Ser68*	stop_gained	Exon 1 of 7	NP_001373322.1	Q9BZ23-4
	PANK2	NM_153638.4		c.533C>A	p.Ser178*	stop_gained	Exon 1 of 7	NP_705902.2	Q9BZ23-1
	PANK2	NM_001324192.1		c.533C>A	p.Ser178*	stop_gained	Exon 1 of 2	NP_001311121.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PANK2	ENST00000610179.7	TSL:1 MANE Select	c.203C>A	p.Ser68*	stop_gained	Exon 1 of 7	ENSP00000477429.2	Q9BZ23-4
	PANK2	ENST00000316562.9	TSL:1	c.533C>A	p.Ser178*	stop_gained	Exon 1 of 7	ENSP00000313377.4	Q9BZ23-1
	PANK2	ENST00000336066.8	TSL:1	n.203C>A		non_coding_transcript_exon	Exon 1 of 7	ENSP00000477229.2	V9GYZ0

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1416584 Hom.: 0 Cov.: 77 AF XY: 0.00000285 AC XY: 2 AN XY: 702734

African (AFR) AF: 0.00 AC: 0 AN: 31936

American (AMR) AF: 0.00 AC: 0 AN: 41068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25382

East Asian (EAS) AF: 0.00 AC: 0 AN: 37914

South Asian (SAS) AF: 0.00 AC: 0 AN: 82922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4790

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1098230

Other (OTH) AF: 0.00 AC: 0 AN: 58906

GnomAD4 genome Cov.: 34

Alfa AF: 0.000932 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Pigmentary pallidal degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Benign	0.090
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.18	N
PhyloP100		-0.070
Vest4		0.79
GERP RS		1.9
PromoterAI		0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137852969; hg19: chr20-3870280; COSMIC: COSV57253055; COSMIC: COSV57253055;