20-3916955-C-G

Variant names:

• chr20-3916955-C-G
• rs137852968
• NM_001386393.1:c.1111C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_001386393.1(PANK2):​c.1111C>G​(p.Arg371Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R371P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PANK2 NM_001386393.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0880
• 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001386393.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-3916956-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 587442.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PANK2	NM_001386393.1	c.1111C>G	p.Arg371Gly	missense_variant	Exon 5 of 7	ENST00000610179.7	NP_001373322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PANK2	ENST00000610179.7	c.1111C>G	p.Arg371Gly	missense_variant	Exon 5 of 7	1	NM_001386393.1	ENSP00000477429.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pigmentary pallidal degeneration Uncertain:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 481 of the PANK2 protein (p.Arg481Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurodegeneration with brain iron accumulation (internal data). ClinVar contains an entry for this variant (Variation ID: 2131133). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PANK2 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg481 amino acid residue in PANK2. Other variant(s) that disrupt this residue have been observed in individuals with PANK2-related conditions (PMID: 16437574, 23166001; internal data), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;.;D;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;.;M;.;.
PhyloP100		-0.088
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.6	D;.;D;.;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.012	D;.;T;.;.
Sift4G	Benign	0.073	T;D;D;D;T
Polyphen		0.90	.;.;P;.;.
Vest4		0.59
MutPred		0.71		.;.;Loss of solvent accessibility (P = 0.0159);.;.;
MVP		0.98
MPC		1.1
ClinPred		0.93	D
GERP RS		3.0
Varity_R		0.87
gMVP		0.77
Mutation Taster		=8/92	disease causing

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: rs137852968; hg19: chr20-3897602;