10-89599486-T-C

Variant names:

• chr10-89599486-T-C
• rs1844710641
• NM_148977.3:c.665A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_148977.3(PANK1):​c.665A>G​(p.His222Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,318 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PANK1 NM_148977.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.665A>G	p.His222Arg	missense	Exon 3 of 7	NP_683878.2	A0A8C8KBT8
	PANK1	NM_148978.3		c.401A>G	p.His134Arg	missense	Exon 3 of 7	NP_683879.1	Q8TE04-2
	PANK1	NM_138316.4		c.401A>G	p.His134Arg	missense	Exon 3 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.665A>G	p.His222Arg	missense	Exon 3 of 7	ENSP00000302108.5	A0A8C8KBT8
	PANK1	ENST00000342512.4	TSL:1	c.401A>G	p.His134Arg	missense	Exon 3 of 7	ENSP00000345118.3	Q8TE04-2
	PANK1	ENST00000322191.10	TSL:1	c.401A>G	p.His134Arg	missense	Exon 3 of 6	ENSP00000318526.6	Q8TE04-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461318 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726870

African (AFR) AF: 0.0000598 AC: 2 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111634

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

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	Benign	0.12
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Benign	0.82
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	0.44	N
PhyloP100		3.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.42
Sift	Benign	0.20	T
Sift4G	Benign	0.61	T
Polyphen		0.0020	B
Vest4		0.37
MutPred		0.65		Loss of stability (P = 0.0935)
MVP		0.91
MPC		1.2
ClinPred		0.43	T
GERP RS		4.7
Varity_R		0.50
gMVP		0.67
Mutation Taster		=56/44	polymorphism

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: rs1844710641; hg19: chr10-91359243; COSMIC: COSV56811053;