NM_001386393.1:c.53G>T

Variant names:

• chr20-3889483-G-T
• rs546381069
• NM_001386393.1:c.53G>T

Variant summary

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

The NM_001386393.1(PANK2):​c.53G>T​(p.Arg18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000748 in 1,336,566 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. R18Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: PANK2 NM_001386393.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04
• 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: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PANK2	NM_001386393.1	MANE Select	c.53G>T	p.Arg18Leu	missense	Exon 1 of 7	NP_001373322.1	Q9BZ23-4
	PANK2	NM_001324191.2		c.-659G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001311120.1	Q9BZ23-2
	PANK2	NM_153638.4		c.383G>T	p.Arg128Leu	missense	Exon 1 of 7	NP_705902.2	Q9BZ23-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PANK2	ENST00000610179.7	TSL:1 MANE Select	c.53G>T	p.Arg18Leu	missense	Exon 1 of 7	ENSP00000477429.2	Q9BZ23-4
	PANK2	ENST00000316562.9	TSL:1	c.383G>T	p.Arg128Leu	missense	Exon 1 of 7	ENSP00000313377.4	Q9BZ23-1
	PANK2	ENST00000336066.8	TSL:1	n.53G>T		non_coding_transcript_exon	Exon 1 of 7	ENSP00000477229.2	V9GYZ0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.48e-7 AC: 1 AN: 1336566 Hom.: 0 Cov.: 79 AF XY: 0.00 AC XY: 0 AN XY: 657276

African (AFR) AF: 0.00 AC: 0 AN: 27904

American (AMR) AF: 0.00 AC: 0 AN: 26910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21562

East Asian (EAS) AF: 0.00 AC: 0 AN: 34396

South Asian (SAS) AF: 0.00 AC: 0 AN: 71970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5174

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1060792

Other (OTH) AF: 0.0000180 AC: 1 AN: 55648

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.059
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	0.0	N
PhyloP100		3.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.30	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.026	D
Sift4G	Benign	0.17	T
Polyphen		0.043	B
Vest4		0.51
MutPred		0.37		Loss of methylation at R128 (P = 0.0011)
MVP		0.94
MPC		0.57
ClinPred		0.69	D
GERP RS		3.8
PromoterAI		0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.42
Mutation Taster		=80/20	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: rs546381069; hg19: chr20-3870130;