NM_001386393.1:c.50G>C

Variant names:

• chr20-3889480-G-C
• rs528149001
• NM_001386393.1:c.50G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001386393.1(PANK2):​c.50G>C​(p.Gly17Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,341,596 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G17V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: PANK2 NM_001386393.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.08
• 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 41 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.17856 (below the threshold of 3.09). Trascript score misZ: -0.052065 (below the threshold of 3.09). GenCC associations: The gene is linked to pantothenate kinase-associated neurodegeneration.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PANK2	NM_001386393.1	MANE Select	c.50G>C	p.Gly17Ala	missense	Exon 1 of 7	NP_001373322.1
	PANK2	NM_153638.4		c.380G>C	p.Gly127Ala	missense	Exon 1 of 7	NP_705902.2
	PANK2	NM_001324192.1		c.380G>C	p.Gly127Ala	missense	Exon 1 of 2	NP_001311121.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PANK2	ENST00000610179.7	TSL:1 MANE Select	c.50G>C	p.Gly17Ala	missense	Exon 1 of 7	ENSP00000477429.2
	PANK2	ENST00000316562.9	TSL:1	c.380G>C	p.Gly127Ala	missense	Exon 1 of 7	ENSP00000313377.4
	PANK2	ENST00000336066.8	TSL:1	n.50G>C		non_coding_transcript_exon	Exon 1 of 7	ENSP00000477229.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000373 AC: 5 AN: 1341596 Hom.: 0 Cov.: 78 AF XY: 0.00000151 AC XY: 1 AN XY: 660160

African (AFR) AF: 0.00 AC: 0 AN: 28234

American (AMR) AF: 0.00 AC: 0 AN: 27692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21802

East Asian (EAS) AF: 0.00 AC: 0 AN: 34576

South Asian (SAS) AF: 0.00 AC: 0 AN: 72702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5202

European-Non Finnish (NFE) AF: 0.00000470 AC: 5 AN: 1063132

Other (OTH) AF: 0.00 AC: 0 AN: 55848

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.059
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	0.0	N
PhyloP100		2.1
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.26
Sift	Uncertain	0.020	D
Sift4G	Benign	0.13	T
Polyphen		0.31	B
Vest4		0.27
MutPred		0.38		Loss of catalytic residue at G127 (P = 0.0468)
MVP		0.97
MPC		0.49
ClinPred		0.49	T
GERP RS		4.7
PromoterAI		0.061	Neutral
Varity_R		0.13
gMVP		0.15
Mutation Taster		=78/22	polymorphism

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: rs528149001; hg19: chr20-3870127;