10-22591745-A-G

Variant names:

• chr10-22591745-A-G
• rs749950706
• NM_005028.5:c.376T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS2

The NM_005028.5(PIP4K2A):​c.376T>C​(p.Ser126Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,684 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S126T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PIP4K2A NM_005028.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.60
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005028.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIP4K2A	NM_005028.5	MANE Select	c.376T>C	p.Ser126Pro	missense	Exon 4 of 10	NP_005019.2
	PIP4K2A	NM_001330062.2		c.199T>C	p.Ser67Pro	missense	Exon 4 of 10	NP_001316991.1	P48426-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIP4K2A	ENST00000376573.9	TSL:1 MANE Select	c.376T>C	p.Ser126Pro	missense	Exon 4 of 10	ENSP00000365757.4	P48426-1
	PIP4K2A	ENST00000545335.5	TSL:2	c.199T>C	p.Ser67Pro	missense	Exon 4 of 10	ENSP00000442098.1	P48426-2
	PIP4K2A	ENST00000928212.1		c.376T>C	p.Ser126Pro	missense	Exon 4 of 8	ENSP00000598271.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460684 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726658

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111340

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		3.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.26
Sift	Benign	0.057	T
Sift4G	Uncertain	0.037	D
Polyphen		0.031	B
Vest4		0.68
MutPred		0.65		Loss of phosphorylation at S126 (P = 0.0377)
MVP		0.19
MPC		0.53
ClinPred		0.95	D
GERP RS		6.0
PromoterAI		-0.15	Neutral
Varity_R		0.78
gMVP		0.58
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs749950706; hg19: chr10-22880674;