20-3889477-G-C

Variant names:

• chr20-3889477-G-C
• rs3737084
• NM_001386393.1:c.47G>C
• PANK2 p.Gly16Ala

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001386393.1(PANK2):​c.47G>C​(p.Gly16Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.872 in 1,523,714 control chromosomes in the GnomAD database, including 580,652 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G16R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.90 (61838 hom., cov: 36)
  • Exomes 𝑓: 0.87 (518814 hom.)
• Consequence: PANK2 NM_001386393.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.760
• Publications: 31 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=1.164075E-6).
• BP6: Variant 20-3889477-G-C is Benign according to our data. Variant chr20-3889477-G-C is described in ClinVar as Benign. ClinVar VariationId is 96526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

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.47G>C	p.Gly16Ala	missense	Exon 1 of 7	NP_001373322.1	Q9BZ23-4
	PANK2	NM_153638.4		c.377G>C	p.Gly126Ala	missense	Exon 1 of 7	NP_705902.2	Q9BZ23-1
	PANK2	NM_001324192.1		c.377G>C	p.Gly126Ala	missense	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.47G>C	p.Gly16Ala	missense	Exon 1 of 7	ENSP00000477429.2	Q9BZ23-4
	PANK2	ENST00000316562.9	TSL:1	c.377G>C	p.Gly126Ala	missense	Exon 1 of 7	ENSP00000313377.4	Q9BZ23-1
	PANK2	ENST00000336066.8	TSL:1	n.47G>C		non_coding_transcript_exon	Exon 1 of 7	ENSP00000477229.2	V9GYZ0

Frequencies

GnomAD3 genomes AF: 0.899 AC: 136790 AN: 152152 Hom.: 61777 Cov.: 36

Gnomad AFR AF: 0.978

Gnomad AMI AF: 0.869

Gnomad AMR AF: 0.932

Gnomad ASJ AF: 0.788

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.772

Gnomad FIN AF: 0.880

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.869

Gnomad OTH AF: 0.914

GnomAD2 exomes AF: 0.862 AC: 110757 AN: 128528 AF XY: 0.853

Gnomad AFR exome AF: 0.983

Gnomad AMR exome AF: 0.932

Gnomad ASJ exome AF: 0.780

Gnomad EAS exome AF: 0.803

Gnomad FIN exome AF: 0.870

Gnomad NFE exome AF: 0.875

Gnomad OTH exome AF: 0.858

GnomAD4 exome AF: 0.869 AC: 1191574 AN: 1371446 Hom.: 518814 Cov.: 86 AF XY: 0.865 AC XY: 585057 AN XY: 676422

African (AFR) AF: 0.982 AC: 30339 AN: 30908

American (AMR) AF: 0.931 AC: 30816 AN: 33096

Ashkenazi Jewish (ASJ) AF: 0.786 AC: 18210 AN: 23160

East Asian (EAS) AF: 0.787 AC: 28459 AN: 36162

South Asian (SAS) AF: 0.764 AC: 58362 AN: 76406

European-Finnish (FIN) AF: 0.873 AC: 29272 AN: 33542

Middle Eastern (MID) AF: 0.832 AC: 4473 AN: 5376

European-Non Finnish (NFE) AF: 0.876 AC: 942292 AN: 1075698

Other (OTH) AF: 0.864 AC: 49351 AN: 57098

GnomAD4 genome AF: 0.899 AC: 136909 AN: 152268 Hom.: 61838 Cov.: 36 AF XY: 0.898 AC XY: 66859 AN XY: 74450

African (AFR) AF: 0.978 AC: 40671 AN: 41574

American (AMR) AF: 0.932 AC: 14275 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 2736 AN: 3472

East Asian (EAS) AF: 0.790 AC: 4071 AN: 5156

South Asian (SAS) AF: 0.773 AC: 3735 AN: 4830

European-Finnish (FIN) AF: 0.880 AC: 9334 AN: 10612

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.869 AC: 59117 AN: 67994

Other (OTH) AF: 0.910 AC: 1925 AN: 2116

Alfa AF: 0.839 Hom.: 5807

Bravo AF: 0.911

Asia WGS AF: 0.809 AC: 2811 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	3	Pigmentary pallidal degeneration (3)
-	-	1	Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.76
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.27
Sift	Benign	1.0	T
Sift4G	Benign	0.77	T
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.15
Mutation Taster		=99/1	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3737084;

hg19: chr20-3870124;

COSMIC: COSV57252830;

COSMIC: COSV57252830;