rs201370957

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.160G>A (NM_005027.4) variant in PIK3R2 is a missense variant predicted to cause substitution of (p.Val54Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.004092 in the European (non Finnish) population, which is higher than the ClinGen BMEP threshold ([>=0.00185]) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: BA1; -8 points (VCEP specifications version 1; Approved: 1/31/2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA9306657/MONDO:0100283/018

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 16 hom. )

Consequence

PIK3R2
NM_005027.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:7

Conservation

PhyloP100: 2.60

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 Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PIK3R2	NM_005027.4 linkuse as main transcript	c.160G>A	p.Val54Met	missense_variant	2/16	ENST00000222254.13	NP_005018.2
PIK3R2	NR_073517.2 linkuse as main transcript	n.715G>A		non_coding_transcript_exon_variant	2/16
PIK3R2	NR_162071.1 linkuse as main transcript	n.715G>A		non_coding_transcript_exon_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PIK3R2	ENST00000222254.13 linkuse as main transcript	c.160G>A	p.Val54Met	missense_variant	2/16	1	NM_005027.4	ENSP00000222254	P1
PIK3R2	ENST00000617130.5 linkuse as main transcript	c.160G>A	p.Val54Met	missense_variant, NMD_transcript_variant	2/15	1		ENSP00000477864
PIK3R2	ENST00000426902.5 linkuse as main transcript	c.160G>A	p.Val54Met	missense_variant, NMD_transcript_variant	1/15	2		ENSP00000395636
PIK3R2	ENST00000617642.2 linkuse as main transcript	c.160G>A	p.Val54Met	missense_variant, NMD_transcript_variant	2/14	5		ENSP00000484714

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

351

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00103

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00420

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00203

AC:

328

AN:

161974

Hom.:

AF XY:

0.00215

AC XY:

190

AN XY:

88192

show subpopulations

Gnomad AFR exome

AF:

0.000722

Gnomad AMR exome

AF:

0.000613

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000423

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00435

Gnomad OTH exome

AF:

0.00247

GnomAD4 exome

AF:

0.00395

AC:

5559

AN:

1408970

Hom.:

Cov.:

AF XY:

0.00384

AC XY:

2673

AN XY:

696366

show subpopulations

Gnomad4 AFR exome

AF:

0.000438

Gnomad4 AMR exome

AF:

0.000590

Gnomad4 ASJ exome

AF:

0.0000795

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000498

Gnomad4 FIN exome

AF:

0.00155

Gnomad4 NFE exome

AF:

0.00489

Gnomad4 OTH exome

AF:

0.00237

GnomAD4 genome

AF:

0.00230

AC:

351

AN:

152360

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

177

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000793

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00103

Gnomad4 NFE

AF:

0.00420

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00334

Hom.:

Bravo

AF:

0.00220

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00118

AC:

ESP6500EA

AF:

0.00411

AC:

ExAC

AF:

0.00164

AC:

188

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PIK3R2: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Brain Malformations Variant Curation Expert Panel

Feb 11, 2022

The c.160G>A (NM_005027.4) variant in PIK3R2 is a missense variant predicted to cause substitution of (p.Val54Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.004092 in the European (non Finnish) population, which is higher than the ClinGen BMEP threshold ([>=0.00185]) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: BA1; -8 points (VCEP specifications version 1; Approved: 1/31/2021) -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

PIK3R2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;T;T

Eigen

Benign

-0.0035

Eigen_PC

Benign

-0.020

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.84

.;T;.

M_CAP

Benign

0.030

MetaRNN

Benign

0.0098

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.;N

MutationTaster

Benign

0.88

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.61

N;.;.

REVEL

Benign

0.059

Sift

Uncertain

0.011

D;.;.

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.98

D;.;D

Vest4

0.27

MVP

0.29

MPC

0.34

ClinPred

0.014

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.13

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