10-89611948-C-A

Variant names:

• chr10-89611948-C-A
• rs1013737590
• NM_148977.3:c.393G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_148977.3(PANK1):​c.393G>T​(p.Glu131Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PANK1 NM_148977.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38060275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PANK1	NM_148977.3	c.393G>T	p.Glu131Asp	missense_variant	Exon 2 of 7	ENST00000307534.10	NP_683878.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PANK1	ENST00000307534.10	c.393G>T	p.Glu131Asp	missense_variant	Exon 2 of 7	1	NM_148977.3	ENSP00000302108.5
PANK1	ENST00000342512.4	c.129G>T	p.Glu43Asp	missense_variant	Exon 2 of 7	1		ENSP00000345118.3
PANK1	ENST00000322191.10	c.129G>T	p.Glu43Asp	missense_variant	Exon 2 of 6	1		ENSP00000318526.6
PANK1	ENST00000461829.1	n.-40G>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461856 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.804G>T (p.E268D) alteration is located in exon 2 (coding exon 2) of the PANK1 gene. This alteration results from a G to T substitution at nucleotide position 804, causing the glutamic acid (E) at amino acid position 268 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.073	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.99	D;B;B
Vest4		0.60
MutPred		0.35		Loss of methylation at K271 (P = 0.075);.;.;
MVP		0.97
MPC		1.5
ClinPred		0.94	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.60

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: rs1013737590; hg19: chr10-91371705;