Genetic Variant PIP4K2A:p.Leu327Val (chr10-22541861-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005028.5(PIP4K2A):c.979C>G(p.Leu327Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L327M) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PIP4K2A
NM_005028.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.753

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2737623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIP4K2A	NM_005028.5 link	c.979C>G	p.Leu327Val	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.979C>G	p.Leu327Val	missense_variant	Exon 8 of 10	1	NM_005028.5	ENSP00000365757.4	P48426-1
PIP4K2A	ENST00000545335.5 link	c.802C>G	p.Leu268Val	missense_variant	Exon 8 of 10	2		ENSP00000442098.1	P48426-2
PIP4K2A	ENST00000323883.11 link	c.559C>G	p.Leu187Val	missense_variant	Exon 6 of 8	2		ENSP00000326294.7	H7BXS3
PIP4K2A	ENST00000604912.1 link	c.*91C>G		downstream_gene_variant		2		ENSP00000473858.1	S4R320

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451568

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721708

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33024

American (AMR)

AF:

0.00

AC:

AN:

42560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25242

East Asian (EAS)

AF:

0.00

AC:

AN:

39608

South Asian (SAS)

AF:

0.00

AC:

AN:

84654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53130

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107716

Other (OTH)

AF:

0.00

AC:

AN:

59934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.049

T;.;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.;.

PhyloP100

0.75

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.89

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.21

T;T;T

Polyphen

0.037

B;.;.

Vest4

0.59

MutPred

0.48

Loss of glycosylation at P326 (P = 0.0831);.;.;

MVP

0.082

MPC

0.86

ClinPred

0.61

GERP RS

-0.31

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.24

gMVP

0.31

Mutation Taster

=82/18

polymorphism

(source)

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

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10-22541861-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over