20-3912514-T-C

Variant names:

• chr20-3912514-T-C
• rs863223343
• NM_001386393.1:c.962T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001324193.2(PANK2):​c.-17T>C variant causes a 5 prime UTR premature start codon gain 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PANK2 NM_001324193.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.20
• Publications: 1 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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 20-3912514-T-C is Pathogenic according to our data. Variant chr20-3912514-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 191359.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001324193.2. 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.962T>C	p.Phe321Ser	missense	Exon 4 of 7	NP_001373322.1	Q9BZ23-4
	PANK2	NM_001324193.2		c.-17T>C		5_prime_UTR_premature_start_codon_gain	Exon 4 of 7	NP_001311122.1
	PANK2	NM_153638.4		c.1292T>C	p.Phe431Ser	missense	Exon 4 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.962T>C	p.Phe321Ser	missense	Exon 4 of 7	ENSP00000477429.2	Q9BZ23-4
	PANK2	ENST00000316562.9	TSL:1	c.1292T>C	p.Phe431Ser	missense	Exon 4 of 7	ENSP00000313377.4	Q9BZ23-1
	PANK2	ENST00000621507.1	TSL:1	c.419T>C	p.Phe140Ser	missense	Exon 4 of 7	ENSP00000481523.1	Q9BZ23-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		6.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.93	P
Vest4		0.82
MutPred		0.93		Gain of disorder (P = 0.005)
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.94
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs863223343; hg19: chr20-3893161;