19-18155913-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005027.4(PIK3R2):c.34C>G(p.Leu12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,412,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L12L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14850998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R2	NM_005027.4	c.34C>G	p.Leu12Val	missense_variant	2/16	ENST00000222254.13
PIK3R2	NR_073517.2	n.589C>G		non_coding_transcript_exon_variant	2/16
PIK3R2	NR_162071.1	n.589C>G		non_coding_transcript_exon_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R2	ENST00000222254.13	c.34C>G	p.Leu12Val	missense_variant	2/16	1	NM_005027.4	P1
PIK3R2	ENST00000617130.5	c.34C>G	p.Leu12Val	missense_variant, NMD_transcript_variant	2/15	1
PIK3R2	ENST00000426902.5	c.34C>G	p.Leu12Val	missense_variant, NMD_transcript_variant	1/15	2
PIK3R2	ENST00000617642.2	c.34C>G	p.Leu12Val	missense_variant, NMD_transcript_variant	2/14	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1412628 Hom.: 0 Cov.: 31 AF XY: 0.00000286 AC XY: 2 AN XY: 698462

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000272

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.20e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The c.34C>G (p.L12V) alteration is located in exon 2 (coding exon 1) of the PIK3R2 gene. This alteration results from a C to G substitution at nucleotide position 34, causing the leucine (L) at amino acid position 12 to be replaced by a valine (V). 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	0.097
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	20
Dann	Benign	0.96
DEOGEN2	Uncertain	0.48	T;T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;.;M
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.90	N;.;.
REVEL	Benign	0.056
Sift	Benign	0.10	T;.;.
Sift4G	Uncertain	0.045	D;D;D
Polyphen		0.0030	B;.;B
Vest4		0.20
MutPred		0.26		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.26
MPC		0.29
ClinPred		0.38	T
GERP RS		0.80
Varity_R		0.14
gMVP		0.45

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: rs1308748759; hg19: chr19-18266723; COSMIC: COSV53221231; COSMIC: COSV53221231;