10-22541861-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005028.5(PIP4K2A):c.979C>A(p.Leu327Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,603,890 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0057 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (6 hom.)
• Consequence: PIP4K2A NM_005028.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.753

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006621033).
• BP6: Variant 10-22541861-G-T is Benign according to our data. Variant chr10-22541861-G-T is described in ClinVar as [Benign]. Clinvar id is 720678.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00567 (863/152322) while in subpopulation AFR AF= 0.019 (788/41560). AF 95% confidence interval is 0.0179. There are 13 homozygotes in gnomad4. There are 425 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 857 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIP4K2A	NM_005028.5	c.979C>A	p.Leu327Met	missense_variant	8/10	ENST00000376573.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIP4K2A	ENST00000376573.9	c.979C>A	p.Leu327Met	missense_variant	8/10	1	NM_005028.5	P1
PIP4K2A	ENST00000545335.5	c.802C>A	p.Leu268Met	missense_variant	8/10	2
PIP4K2A	ENST00000323883.11	c.559C>A	p.Leu187Met	missense_variant	6/8	2

Frequencies

GnomAD3 genomes AF: 0.00563 AC: 857 AN: 152204 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00157 AC: 378 AN: 240364 Hom.: 3 AF XY: 0.00125 AC XY: 162 AN XY: 129888

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000348

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.000564 AC: 818 AN: 1451568 Hom.: 6 Cov.: 33 AF XY: 0.000489 AC XY: 353 AN XY: 721708

Gnomad4 AFR exome AF: 0.0199

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000591

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00567 AC: 863 AN: 152322 Hom.: 13 Cov.: 32 AF XY: 0.00571 AC XY: 425 AN XY: 74496

Gnomad4 AFR AF: 0.0190

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000947 Hom.: 4

Bravo AF: 0.00719

ESP6500AA AF: 0.0188 AC: 83

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00185 AC: 224

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	11
Dann	Uncertain	0.99
DEOGEN2	Benign	0.058	T;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.0066	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.29	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.20	B;.;.
Vest4		0.48
MVP		0.068
MPC		0.64
ClinPred		0.0091	T
GERP RS		-0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.24

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: rs2230470; hg19: chr10-22830790;