NM_005027.4:c.451C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005027.4(PIK3R2):c.451C>T(p.Pro151Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,612,186 control chromosomes in the GnomAD database, including 164 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P151P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0045 ( 20 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 144 hom. )

Consequence

PIK3R2
NM_005027.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.35

Publications

5 publications found

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 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024369657).

BP6

Variant 19-18160954-C-T is Benign according to our data. Variant chr19-18160954-C-T is described in ClinVar as Benign. ClinVar VariationId is 235784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R2	NM_005027.4 link	c.451C>T	p.Pro151Ser	missense_variant	Exon 4 of 16	ENST00000222254.13	NP_005018.2	O00459
PIK3R2	NR_073517.2 link	n.1006C>T		non_coding_transcript_exon_variant	Exon 4 of 16
PIK3R2	NR_162071.1 link	n.1006C>T		non_coding_transcript_exon_variant	Exon 4 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R2	ENST00000222254.13 link	c.451C>T	p.Pro151Ser	missense_variant	Exon 4 of 16	1	NM_005027.4	ENSP00000222254.6		O00459
ENSG00000268173	ENST00000593731.1 link	n.451C>T		non_coding_transcript_exon_variant	Exon 4 of 25	2		ENSP00000471914.1

Frequencies

GnomAD3 genomes

AF:

0.00443

AC:

675

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0389

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00674

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.0122

AC:

2977

AN:

244948

AF XY:

0.00892

show subpopulations

Gnomad AFR exome

AF:

0.000651

Gnomad AMR exome

AF:

0.0797

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000544

Gnomad OTH exome

AF:

0.00838

GnomAD4 exome

AF:

0.00266

AC:

3878

AN:

1459844

Hom.:

144

Cov.:

AF XY:

0.00221

AC XY:

1606

AN XY:

726142

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33464

American (AMR)

AF:

0.0724

AC:

3222

AN:

44502

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26080

East Asian (EAS)

AF:

0.0119

AC:

472

AN:

39674

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1111588

Other (OTH)

AF:

0.00219

AC:

132

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

204

409

613

818

1022

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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:

0.00448

AC:

682

AN:

152342

Hom.:

Cov.:

AF XY:

0.00514

AC XY:

383

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000673

AC:

AN:

41576

American (AMR)

AF:

0.0393

AC:

601

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00675

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68022

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

101

135

169

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:

0.00125

Hom.:

Bravo

AF:

0.00770

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00924

AC:

1119

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1

Benign:1

Jan 29, 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

0.14

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.064

T;T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.70

.;T;.

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.9

N;.;N

PhyloP100

1.3

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.46

N;.;.

REVEL

Benign

0.13

Sift

Benign

0.74

T;.;.

Sift4G

Benign

0.46

T;T;T

Polyphen

0.0060

B;.;B

Vest4

0.29

MPC

0.29

ClinPred

0.0080

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.20

Mutation Taster

=96/4

polymorphism (auto)

(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