19-18155910-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BS1_Supporting

The NM_005027.4(PIK3R2):c.31G>T(p.Ala11Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,411,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

Genes affected

PIK3R2 (HGNC:8980): (phosphoinositide-3-kinase regulatory subunit 2) Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates phosphatidylinositol and similar compounds, creating second messengers important in growth signaling pathways. PI3K functions as a heterodimer of a regulatory and a catalytic subunit. The protein encoded by this gene is a regulatory component of PI3K. Three transcript variants, one protein coding and the other two non-protein coding, have been found for this gene. [provided by RefSeq, Apr 2019]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37260187).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000113 (16/1411080) while in subpopulation SAS AF= 0.000186 (15/80450). AF 95% confidence interval is 0.000115. There are 0 homozygotes in gnomad4_exome. There are 12 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R2	NM_005027.4	c.31G>T	p.Ala11Ser	missense_variant	2/16	ENST00000222254.13
PIK3R2	NR_073517.2	n.586G>T		non_coding_transcript_exon_variant	2/16
PIK3R2	NR_162071.1	n.586G>T		non_coding_transcript_exon_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R2	ENST00000222254.13	c.31G>T	p.Ala11Ser	missense_variant	2/16	1	NM_005027.4	P1
PIK3R2	ENST00000617130.5	c.31G>T	p.Ala11Ser	missense_variant, NMD_transcript_variant	2/15	1
PIK3R2	ENST00000426902.5	c.31G>T	p.Ala11Ser	missense_variant, NMD_transcript_variant	1/15	2
PIK3R2	ENST00000617642.2	c.31G>T	p.Ala11Ser	missense_variant, NMD_transcript_variant	2/14	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000179 AC: 3 AN: 167506 Hom.: 0 AF XY: 0.0000330 AC XY: 3 AN XY: 90854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000126

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000113 AC: 16 AN: 1411080 Hom.: 0 Cov.: 31 AF XY: 0.0000172 AC XY: 12 AN XY: 697572

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: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.21e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000176 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 14, 2023

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 11 of the PIK3R2 protein (p.Ala11Ser). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PIK3R2 protein function. This variant has not been reported in the literature in individuals affected with PIK3R2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	0.00014	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.38	T;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.0	N;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.071	T;.;.
Sift4G	Uncertain	0.053	T;T;T
Polyphen		1.0	D;.;D
Vest4		0.43
MutPred		0.40		Gain of phosphorylation at A11 (P = 0.0296);Gain of phosphorylation at A11 (P = 0.0296);Gain of phosphorylation at A11 (P = 0.0296);
MVP		0.58
MPC		0.53
ClinPred		0.75	D
GERP RS		4.3
Varity_R		0.36
gMVP		0.55

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: rs751392338; hg19: chr19-18266720;