17-38777729-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_003559.5(PIP4K2B):c.765G>C(p.Glu255Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/18 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)
• Consequence: PIP4K2B NM_003559.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.423

Genes affected

PIP4K2B (HGNC:8998): (phosphatidylinositol-5-phosphate 4-kinase type 2 beta) The protein encoded by this gene catalyzes the phosphorylation of phosphatidylinositol-5-phosphate on the fourth hydroxyl of the myo-inositol ring to form phosphatidylinositol-5,4-bisphosphate. This gene is a member of the phosphatidylinositol-5-phosphate 4-kinase family. The encoded protein sequence does not show similarity to other kinases, but the protein does exhibit kinase activity. Additionally, the encoded protein interacts with p55 TNF receptor. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PIP4K2B
• BP4: Computational evidence support a benign effect (MetaRNN=0.05605614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIP4K2B	NM_003559.5	c.765G>C	p.Glu255Asp	missense_variant	7/10	ENST00000619039.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIP4K2B	ENST00000619039.5	c.765G>C	p.Glu255Asp	missense_variant	7/10	1	NM_003559.5	P1
PIP4K2B	ENST00000613767.4	n.337G>C		non_coding_transcript_exon_variant	4/5	4
PIP4K2B	ENST00000617781.1	n.863G>C		non_coding_transcript_exon_variant	7/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 21, 2023

The c.765G>C (p.E255D) alteration is located in exon 7 (coding exon 7) of the PIP4K2B gene. This alteration results from a G to C substitution at nucleotide position 765, causing the glutamic acid (E) at amino acid position 255 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	0.054
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	14
Dann	Uncertain	0.97
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.70	D
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.23	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
Sift4G	Benign	0.72	T
Polyphen		0.0010	B
Vest4		0.24
MutPred		0.43		Loss of methylation at K258 (P = 0.0944);
MVP		0.043
ClinPred		0.39	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.23

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

Other links and lift over

dbSNP: rs1425630895; hg19: chr17-36933982;