Genetic Variant NM_005028.5:c.1001C>T (chr10-22541839-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005028.5(PIP4K2A):c.1001C>T(p.Pro334Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,580,112 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

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

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

PIP4K2A
NM_005028.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.60

Variant links:

Genes affected

PIP4K2A (HGNC:8997): (phosphatidylinositol-5-phosphate 4-kinase type 2 alpha) Phosphatidylinositol-5,4-bisphosphate, the precursor to second messengers of the phosphoinositide signal transduction pathways, is thought to be involved in the regulation of secretion, cell proliferation, differentiation, and motility. The protein encoded by this gene is one of a family of enzymes capable of catalyzing the phosphorylation of phosphatidylinositol-5-phosphate on the fourth hydroxyl of the myo-inositol ring to form phosphatidylinositol-5,4-bisphosphate. The amino acid sequence of this enzyme does not show homology to other kinases, but the recombinant protein does exhibit kinase activity. This gene is a member of the phosphatidylinositol-5-phosphate 4-kinase family. [provided by RefSeq, Jul 2008]

PIP4K2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIP4K2A	NM_005028.5 link	c.1001C>T	p.Pro334Leu	missense_variant	Exon 8 of 10	ENST00000376573.9	NP_005019.2	P48426-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PIP4K2A	ENST00000376573.9 link	c.1001C>T	p.Pro334Leu	missense_variant	Exon 8 of 10	1	NM_005028.5	ENSP00000365757.4	P48426-1
PIP4K2A	ENST00000545335.5 link	c.824C>T	p.Pro275Leu	missense_variant	Exon 8 of 10	2		ENSP00000442098.1	P48426-2
PIP4K2A	ENST00000323883.11 link	c.581C>T	p.Pro194Leu	missense_variant	Exon 6 of 8	2		ENSP00000326294.7	H7BXS3
PIP4K2A	ENST00000604912.1 link	c.*113C>T		downstream_gene_variant		2		ENSP00000473858.1	S4R320

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000449

AC:

AN:

222630

Hom.:

AF XY:

0.00000833

AC XY:

AN XY:

120016

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000572

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000630

AC:

AN:

1427840

Hom.:

Cov.:

AF XY:

0.00000848

AC XY:

AN XY:

707960

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000508

Gnomad4 SAS exome

AF:

0.0000124

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000456

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000604

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;.;.

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.2

L;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.1

D;D;D

REVEL

Uncertain

0.38

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.024

B;.;.

Vest4

0.81

MutPred

0.56

Loss of sheet (P = 0.0181);.;.;

MVP

0.52

MPC

0.42

ClinPred

0.75

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.62

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over