10-22541988-C-A

Position:

• chr10-22541988-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005028.5(PIP4K2A):​c.852G>T​(p.Glu284Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PIP4K2A NM_005028.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16853148).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIP4K2A	NM_005028.5	c.852G>T	p.Glu284Asp	missense_variant	8/10	ENST00000376573.9	NP_005019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIP4K2A	ENST00000376573.9	c.852G>T	p.Glu284Asp	missense_variant	8/10	1	NM_005028.5	ENSP00000365757	P1
PIP4K2A	ENST00000545335.5	c.675G>T	p.Glu225Asp	missense_variant	8/10	2		ENSP00000442098
PIP4K2A	ENST00000323883.11	c.432G>T	p.Glu144Asp	missense_variant	6/8	2		ENSP00000326294
PIP4K2A	ENST00000604912.1	c.390G>T	p.Glu130Asp	missense_variant	5/5	2		ENSP00000473858

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461810 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727198

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: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2024

The c.852G>T (p.E284D) alteration is located in exon 8 (coding exon 8) of the PIP4K2A gene. This alteration results from a G to T substitution at nucleotide position 852, causing the glutamic acid (E) at amino acid position 284 to be replaced by an aspartic acid (D). 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	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.036	T;.;.;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.66	T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.21	N;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.67	N;N;N;.
REVEL	Benign	0.064
Sift	Benign	0.59	T;T;T;.
Sift4G	Benign	0.73	T;T;T;T
Polyphen		0.0040	B;.;.;.
Vest4		0.39
MutPred		0.43		Gain of catalytic residue at E284 (P = 0.0218);.;.;.;
MVP		0.068
MPC		0.36
ClinPred		0.29	T
GERP RS		4.2
Varity_R		0.33
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-22830917;