rs201370957

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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

Publications

13 publications found

Variant links:

COSMIC-nc: COSV105838506

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 Gene-Disease associations (from GenCC):

megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P, Genomics England PanelApp
overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PIK3R2 links:

ENSG00000268173 (HGNC:):

ENSG00000268173 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R2	NM_005027.4 link	c.160G>A	p.Val54Met	missense_variant	Exon 2 of 16	ENST00000222254.13	NP_005018.2	O00459
PIK3R2	NR_073517.2 link	n.715G>A		non_coding_transcript_exon_variant	Exon 2 of 16
PIK3R2	NR_162071.1 link	n.715G>A		non_coding_transcript_exon_variant	Exon 2 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R2	ENST00000222254.13 link	c.160G>A	p.Val54Met	missense_variant	Exon 2 of 16	1	NM_005027.4	ENSP00000222254.6		O00459
ENSG00000268173	ENST00000593731.1 link	n.160G>A		non_coding_transcript_exon_variant	Exon 2 of 25	2		ENSP00000471914.1

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

GnomAD2 exomes

AF:

0.00203

AC:

328

AN:

161974

AF XY:

0.00215

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 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

African (AFR)

AF:

0.000438

AC:

AN:

31958

American (AMR)

AF:

0.000590

AC:

AN:

37270

Ashkenazi Jewish (ASJ)

AF:

0.0000795

AC:

AN:

25142

East Asian (EAS)

AF:

0.00

AC:

AN:

36590

South Asian (SAS)

AF:

0.0000498

AC:

AN:

80276

European-Finnish (FIN)

AF:

0.00155

AC:

AN:

48398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00489

AC:

5304

AN:

1085334

Other (OTH)

AF:

0.00237

AC:

138

AN:

58300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

369

738

1108

1477

1846

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

204

408

612

816

1020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00230

AC:

351

AN:

152360

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

177

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000793

AC:

AN:

41594

American (AMR)

AF:

0.00111

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00103

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00420

AC:

286

AN:

68026

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00327

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

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PIK3R2: BS2 -

Oct 30, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 11, 2022

ClinGen Brain Malformations Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

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

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PIK3R2-related disorder

Benign:1

Jun 28, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

2.6

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

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over