20-3918717-C-G

Variant names:

• chr20-3918717-C-G
• rs137852967
• NM_001386393.1:c.1253C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3 PP5

The NM_001386393.1(PANK2):​c.1253C>G​(p.Thr418Arg) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T418M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PANK2 NM_001386393.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.14
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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 chr20-3918717-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.766
• PP5: Variant 20-3918717-C-G is Pathogenic according to our data. Variant chr20-3918717-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3233574.

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.1253C>G	p.Thr418Arg	missense	Exon 6 of 7	NP_001373322.1	Q9BZ23-4
	PANK2	NM_153638.4		c.1583C>G	p.Thr528Arg	missense	Exon 6 of 7	NP_705902.2	Q9BZ23-1
	PANK2	NM_001324191.2		c.710C>G	p.Thr237Arg	missense	Exon 7 of 8	NP_001311120.1	Q9BZ23-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PANK2	ENST00000610179.7	TSL:1 MANE Select	c.1253C>G	p.Thr418Arg	missense	Exon 6 of 7	ENSP00000477429.2	Q9BZ23-4
	PANK2	ENST00000316562.9	TSL:1	c.1583C>G	p.Thr528Arg	missense	Exon 6 of 7	ENSP00000313377.4	Q9BZ23-1
	PANK2	ENST00000621507.1	TSL:1	c.710C>G	p.Thr237Arg	missense	Exon 6 of 7	ENSP00000481523.1	Q9BZ23-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
1	-	-	Pigmentary pallidal degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	0.060
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.0	L
PhyloP100		6.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.65
Sift	Benign	0.52	T
Sift4G	Benign	0.62	T
Polyphen		0.75	P
Vest4		0.79
MutPred		0.55		Gain of MoRF binding (P = 0.0082)
MVP		0.97
MPC		1.0
ClinPred		0.86	D
GERP RS		3.2
Varity_R		0.63
gMVP		0.85
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137852967; hg19: chr20-3899364;