10-22540071-G-C

Variant names:

• chr10-22540071-G-C
• NM_005028.5:c.1040C>G

Variant summary

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

The NM_005028.5(PIP4K2A):​c.1040C>G​(p.Ser347Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIP4K2A NM_005028.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.59

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]

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=0.3724844).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIP4K2A	NM_005028.5	c.1040C>G	p.Ser347Trp	missense_variant	Exon 9 of 10	ENST00000376573.9	NP_005019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIP4K2A	ENST00000376573.9	c.1040C>G	p.Ser347Trp	missense_variant	Exon 9 of 10	1	NM_005028.5	ENSP00000365757.4
PIP4K2A	ENST00000545335.5	c.863C>G	p.Ser288Trp	missense_variant	Exon 9 of 10	2		ENSP00000442098.1
PIP4K2A	ENST00000323883.11	c.620C>G	p.Ser207Trp	missense_variant	Exon 7 of 8	2		ENSP00000326294.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1040C>G (p.S347W) alteration is located in exon 9 (coding exon 9) of the PIP4K2A gene. This alteration results from a C to G substitution at nucleotide position 1040, causing the serine (S) at amino acid position 347 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	Pathogenic	0.81
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.95	P;.;.
Vest4		0.39
MutPred		0.50		Loss of disorder (P = 0.0212);.;.;
MVP		0.23
MPC		1.3
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.72
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-22829000;