10-22541839-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_005028.5(PIP4K2A):c.1001C>G(p.Pro334Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000049 in 1,427,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

PIP4K2A
NM_005028.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIP4K2A	NM_005028.5 link	c.1001C>G	p.Pro334Arg	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>G	p.Pro334Arg	missense_variant	Exon 8 of 10	1	NM_005028.5	ENSP00000365757.4	P48426-1
PIP4K2A	ENST00000545335.5 link	c.824C>G	p.Pro275Arg	missense_variant	Exon 8 of 10	2		ENSP00000442098.1	P48426-2
PIP4K2A	ENST00000323883.11 link	c.581C>G	p.Pro194Arg	missense_variant	Exon 6 of 8	2		ENSP00000326294.7	H7BXS3
PIP4K2A	ENST00000604912.1 link	c.*113C>G		downstream_gene_variant		2		ENSP00000473858.1	S4R320

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000135

AC:

AN:

222630

AF XY:

0.0000167

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000490

AC:

AN:

1427840

Hom.:

Cov.:

AF XY:

0.00000706

AC XY:

AN XY:

707960

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32184

American (AMR)

AF:

0.0000775

AC:

AN:

38696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23514

East Asian (EAS)

AF:

0.00

AC:

AN:

39332

South Asian (SAS)

AF:

0.00

AC:

AN:

80698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5590

European-Non Finnish (NFE)

AF:

0.00000365

AC:

AN:

1096568

Other (OTH)

AF:

0.00

AC:

AN:

58866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1001C>G (p.P334R) alteration is located in exon 8 (coding exon 8) of the PIP4K2A gene. This alteration results from a C to G substitution at nucleotide position 1001, causing the proline (P) at amino acid position 334 to be replaced by an arginine (R). 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

0.25

BayesDel_addAF

Uncertain

0.048

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.018

MetaRNN

Pathogenic

0.77

D;D;D

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.4

M;.;.

PhyloP100

9.6

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.1

D;D;D

REVEL

Uncertain

0.39

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.20

B;.;.

Vest4

0.85

MutPred

0.52

Gain of helix (P = 0.027);.;.;

MVP

0.38

MPC

0.73

ClinPred

0.85

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.67

Mutation Taster

=36/64

disease causing

(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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10-22541839-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over