10-89593209-G-C

Variant names:

• chr10-89593209-G-C
• rs2296616
• NM_148977.3:c.1188C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_148977.3(PANK1):​c.1188C>G​(p.Cys396Trp) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PANK1 NM_148977.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.20

Genes affected

PANK1 (HGNC:8598): (pantothenate kinase 1) This gene encodes a member of the pantothenate kinase family. Pantothenate kinases are key regulatory enzymes in the biosynthesis of coenzyme A (CoA). The encoded protein catalyzes the first and rate-limiting enzymatic reaction in CoA biosynthesis and is regulated by CoA through feedback inhibition. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. This gene and an intronic miRNA on the same strand are co-regulated by the tumor suppressor p53 (see PMID 20833636). [provided by RefSeq, Apr 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PANK1	NM_148977.3	c.1188C>G	p.Cys396Trp	missense_variant	Exon 5 of 7	ENST00000307534.10	NP_683878.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PANK1	ENST00000307534.10	c.1188C>G	p.Cys396Trp	missense_variant	Exon 5 of 7	1	NM_148977.3	ENSP00000302108.5
PANK1	ENST00000342512.4	c.924C>G	p.Cys308Trp	missense_variant	Exon 5 of 7	1		ENSP00000345118.3
PANK1	ENST00000322191.10	c.747C>G	p.Cys249Trp	missense_variant	Exon 4 of 6	1		ENSP00000318526.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-9.9	D;D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.084	T;D;D
Sift4G	Uncertain	0.023	D;D;T
Polyphen		1.0	D;D;D
Vest4		0.82
MutPred		0.55		Gain of MoRF binding (P = 0.026);.;.;
MVP		0.97
MPC		1.9
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs2296616; hg19: chr10-91352966;