10-89611823-A-C

Variant names:

• chr10-89611823-A-C
• NM_148977.3:c.518T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_148977.3(PANK1):​c.518T>G​(p.Ile173Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. I173T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PANK1 NM_148977.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.21
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_148977.3. 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
	PANK1	NM_148977.3	MANE Select	c.518T>G	p.Ile173Ser	missense	Exon 2 of 7	NP_683878.2	A0A8C8KBT8
	PANK1	NM_148978.3		c.254T>G	p.Ile85Ser	missense	Exon 2 of 7	NP_683879.1	Q8TE04-2
	PANK1	NM_138316.4		c.254T>G	p.Ile85Ser	missense	Exon 2 of 6	NP_612189.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PANK1	ENST00000307534.10	TSL:1 MANE Select	c.518T>G	p.Ile173Ser	missense	Exon 2 of 7	ENSP00000302108.5	A0A8C8KBT8
	PANK1	ENST00000342512.4	TSL:1	c.254T>G	p.Ile85Ser	missense	Exon 2 of 7	ENSP00000345118.3	Q8TE04-2
	PANK1	ENST00000322191.10	TSL:1	c.254T>G	p.Ile85Ser	missense	Exon 2 of 6	ENSP00000318526.6	Q8TE04-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		9.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.74		Loss of stability (P = 0.0339)
MVP		0.99
MPC		1.9
ClinPred		0.99	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.96
Mutation Taster		=6/94	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

hg19: chr10-91371580;