19-18155925-C-G

Position:

chr19-18155925-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005027.4(PIK3R2):c.46C>G(p.Arg16Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000447 in 1,567,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. R16C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

PIK3R2
NM_005027.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.66

Variant links:

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]

PIK3R2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16274023).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PIK3R2	NM_005027.4 linkuse as main transcript	c.46C>G	p.Arg16Gly	missense_variant	2/16	ENST00000222254.13
PIK3R2	NR_073517.2 linkuse as main transcript	n.601C>G		non_coding_transcript_exon_variant	2/16
PIK3R2	NR_162071.1 linkuse as main transcript	n.601C>G		non_coding_transcript_exon_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PIK3R2	ENST00000222254.13 linkuse as main transcript	c.46C>G	p.Arg16Gly	missense_variant	2/16	1	NM_005027.4	P1
PIK3R2	ENST00000617130.5 linkuse as main transcript	c.46C>G	p.Arg16Gly	missense_variant, NMD_transcript_variant	2/15	1
PIK3R2	ENST00000426902.5 linkuse as main transcript	c.46C>G	p.Arg16Gly	missense_variant, NMD_transcript_variant	1/15	2
PIK3R2	ENST00000617642.2 linkuse as main transcript	c.46C>G	p.Arg16Gly	missense_variant, NMD_transcript_variant	2/14	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00000580

AC:

AN:

172388

Hom.:

AF XY:

0.0000107

AC XY:

AN XY:

93736

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000145

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000424

AC:

AN:

1415356

Hom.:

Cov.:

AF XY:

0.00000857

AC XY:

AN XY:

700132

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000395

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000459

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 05, 2023

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 16 of the PIK3R2 protein (p.Arg16Gly). 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. This variant has not been reported in the literature in individuals affected with PIK3R2-related conditions. 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

T;T;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.023

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.;L

MutationTaster

Benign

0.95

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.3

N;.;.

REVEL

Benign

0.078

Sift

Uncertain

0.011

D;.;.

Sift4G

Uncertain

0.026

D;D;D

Polyphen

0.36

B;.;B

Vest4

0.33

MutPred

0.20

Loss of solvent accessibility (P = 0.1235);Loss of solvent accessibility (P = 0.1235);Loss of solvent accessibility (P = 0.1235);

MVP

0.39

MPC

0.43

ClinPred

0.44

GERP RS

2.2

Varity_R

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over