19-18155935-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_005027.4(PIK3R2):c.56G>A(p.Arg19Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000172 in 1,570,076 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R19W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015589118).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000176 (25/1417816) while in subpopulation MID AF= 0.00035 (2/5710). AF 95% confidence interval is 0.0000674. There are 0 homozygotes in gnomad4_exome. There are 14 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
• BS2: High AC in GnomAdExome at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R2	NM_005027.4	c.56G>A	p.Arg19Gln	missense_variant	2/16	ENST00000222254.13
PIK3R2	NR_073517.2	n.611G>A		non_coding_transcript_exon_variant	2/16
PIK3R2	NR_162071.1	n.611G>A		non_coding_transcript_exon_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R2	ENST00000222254.13	c.56G>A	p.Arg19Gln	missense_variant	2/16	1	NM_005027.4	P1
PIK3R2	ENST00000617130.5	c.56G>A	p.Arg19Gln	missense_variant, NMD_transcript_variant	2/15	1
PIK3R2	ENST00000426902.5	c.56G>A	p.Arg19Gln	missense_variant, NMD_transcript_variant	1/15	2
PIK3R2	ENST00000617642.2	c.56G>A	p.Arg19Gln	missense_variant, NMD_transcript_variant	2/14	5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152260 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000401 AC: 7 AN: 174512 Hom.: 0 AF XY: 0.0000210 AC XY: 2 AN XY: 95072

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000218

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000409

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000176 AC: 25 AN: 1417816 Hom.: 0 Cov.: 31 AF XY: 0.0000200 AC XY: 14 AN XY: 701572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000155

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000269

Gnomad4 SAS exome AF: 0.0000247

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74390

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000522 AC: 6

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 09, 2023

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 not expected to disrupt PIK3R2 protein function. ClinVar contains an entry for this variant (Variation ID: 1037102). This variant has not been reported in the literature in individuals affected with PIK3R2-related conditions. This variant is present in population databases (rs754693011, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 19 of the PIK3R2 protein (p.Arg19Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.60
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;T
Eigen	Benign	0.0084
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.030	N;.;N
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.81	N;.;.
REVEL	Benign	0.046
Sift	Benign	0.094	T;.;.
Sift4G	Benign	0.15	T;T;T
Polyphen		0.25	B;.;B
Vest4		0.11
MutPred		0.28		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.33
MPC		0.36
ClinPred		0.13	T
GERP RS		4.5
Varity_R		0.64
gMVP		0.30

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: rs754693011; hg19: chr19-18266745; COSMIC: COSV53218559; COSMIC: COSV53218559;