chr20-3918717-C-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• 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 Lovd as [Likely_pathogenic].
• 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 id is 3233574.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr20-3918717-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PANK2	NM_001386393.1	c.1253C>G	p.Thr418Arg	missense_variant	Exon 6 of 7	ENST00000610179.7	NP_001373322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PANK2	ENST00000610179.7	c.1253C>G	p.Thr418Arg	missense_variant	Exon 6 of 7	1	NM_001386393.1	ENSP00000477429.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pigmentary pallidal degeneration Pathogenic:1

Mar 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Mar 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PANK2 c.1583C>G (p.Thr528Arg), also known as c.1253C>G (p.Thr418Arg), results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251482 control chromosomes (gnomAD). c.1583C>G has been reported in the literature in an individual affected with Pantothenate Kinase-Associated Neurodegeneration (Sakpichaisakul_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Another missense change affecting this residue has been classified as pathogenic, suggesting this may be a functionally important residue. The following publication has been ascertained in the context of this evaluation (PMID: 31088771). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.0	.;.;L;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.2	N;.;N;.;.
REVEL	Pathogenic	0.65
Sift	Benign	0.52	T;.;T;.;.
Sift4G	Benign	0.62	T;T;T;T;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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-3899364;