Genetic Variant PANK1:c.-198G>T (chr10-89645089-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_148977.3(PANK1):c.-198G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000314 in 1,494,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

PANK1
NM_148977.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.20

Variant links:

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]

PANK1 links:

PANK1-AS1 (HGNC:55718): (PANK1 antisense RNA 1)

PANK1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PANK1	NM_148977.3 link	c.-198G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	ENST00000307534.10	NP_683878.2	Q8TE04
PANK1	NM_148977.3 link	c.-198G>T		5_prime_UTR_variant	Exon 1 of 7	ENST00000307534.10	NP_683878.2	Q8TE04

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PANK1	ENST00000307534.10 link	c.-198G>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	1	NM_148977.3	ENSP00000302108.5	A0A8C8KBT8
PANK1	ENST00000307534.10 link	c.-198G>T	5_prime_UTR_variant	Exon 1 of 7	1	NM_148977.3	ENSP00000302108.5	A0A8C8KBT8
PANK1-AS1	ENST00000454174.5 link	n.-193C>A	upstream_gene_variant		2
PANK1-AS1	ENST00000660192.1 link	n.-183C>A	upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000390

AC:

AN:

102566

Hom.:

AF XY:

0.0000339

AC XY:

AN XY:

58996

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000862

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000320

AC:

AN:

1342820

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

663520

show subpopulations

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:

0.0000395

Gnomad4 OTH exome

AF:

0.0000181

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000629

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000372

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.214G>T (p.G72W) alteration is located in exon 1 (coding exon 1) of the PANK1 gene. This alteration results from a G to T substitution at nucleotide position 214, causing the glycine (G) at amino acid position 72 to be replaced by a tryptophan (W). 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

Benign

0.12

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

8.1

DANN

Benign

0.80

DEOGEN2

Benign

0.15

Eigen

Benign

-0.89

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.38

M_CAP

Pathogenic

0.98

MetaRNN

Uncertain

0.66

MetaSVM

Uncertain

0.65

MutationAssessor

Benign

0.69

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.0

REVEL

Uncertain

0.34

Sift

Uncertain

0.0020

Sift4G

Benign

0.18

Polyphen

0.99

Vest4

0.46

MutPred

0.37

Loss of methylation at R71 (P = 0.0183);

MVP

0.81

MPC

0.71

ClinPred

0.096

GERP RS

-2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.069

gMVP

0.099

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over