20-3889480-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001386393.1(PANK2):​c.50G>T​(p.Gly17Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000809 in 1,493,912 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G17S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00082 (13 hom.)
• Consequence: PANK2 NM_001386393.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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: Benign. The variant received -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008071929).
• BP6: Variant 20-3889480-G-T is Benign according to our data. Variant chr20-3889480-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 285843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00067 (102/152318) while in subpopulation SAS AF = 0.00952 (46/4830). AF 95% confidence interval is 0.00734. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

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>T	p.Gly17Val	missense	Exon 1 of 7	NP_001373322.1
	PANK2	NM_153638.4		c.380G>T	p.Gly127Val	missense	Exon 1 of 7	NP_705902.2
	PANK2	NM_001324192.1		c.380G>T	p.Gly127Val	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>T	p.Gly17Val	missense	Exon 1 of 7	ENSP00000477429.2
	PANK2	ENST00000316562.9	TSL:1	c.380G>T	p.Gly127Val	missense	Exon 1 of 7	ENSP00000313377.4
	PANK2	ENST00000336066.8	TSL:1	n.50G>T		non_coding_transcript_exon	Exon 1 of 7	ENSP00000477229.2

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152204 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00173 AC: 167 AN: 96748 AF XY: 0.00204

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000297

Gnomad ASJ exome AF: 0.00114

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000697

Gnomad OTH exome AF: 0.00176

GnomAD4 exome AF: 0.000824 AC: 1106 AN: 1341594 Hom.: 13 Cov.: 78 AF XY: 0.00104 AC XY: 684 AN XY: 660158

African (AFR) AF: 0.000177 AC: 5 AN: 28234

American (AMR) AF: 0.000289 AC: 8 AN: 27692

Ashkenazi Jewish (ASJ) AF: 0.000505 AC: 11 AN: 21802

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

South Asian (SAS) AF: 0.00829 AC: 603 AN: 72702

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

Middle Eastern (MID) AF: 0.00519 AC: 27 AN: 5202

European-Non Finnish (NFE) AF: 0.000368 AC: 391 AN: 1063130

Other (OTH) AF: 0.00109 AC: 61 AN: 55848

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152318 Hom.: 0 Cov.: 34 AF XY: 0.000712 AC XY: 53 AN XY: 74478

African (AFR) AF: 0.0000721 AC: 3 AN: 41590

American (AMR) AF: 0.000719 AC: 11 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00952 AC: 46 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68006

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000505 Hom.: 1

Bravo AF: 0.000487

ExAC AF: 0.00153 AC: 158

Asia WGS AF: 0.00260 AC: 9 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Pigmentary pallidal degeneration (2)
-	-	1	not specified (1)
-	-	1	PANK2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0081	T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	0.0	N
PhyloP100		2.1
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.51	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.020	D
Polyphen		0.61	P
Vest4		0.43
MVP		0.98
MPC		0.62
ClinPred		0.083	T
GERP RS		4.7
PromoterAI		-0.0059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.15
Mutation Taster		=74/26	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;