chr19-18162237-T-C

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.937T>C(p.Ser313Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.95 in 1,601,454 control chromosomes in the GnomAD database, including 722,944 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S313A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.96 ( 69490 hom., cov: 32)

Exomes 𝑓: 0.95 ( 653454 hom. )

Consequence

PIK3R2
NM_005027.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.00200

Publications

54 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=1.0996432E-6).

BP6

Variant 19-18162237-T-C is Benign according to our data. Variant chr19-18162237-T-C is described in ClinVar as [Benign]. Clinvar id is 803546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R2	NM_005027.4 link	c.937T>C	p.Ser313Pro	missense_variant	Exon 8 of 16	ENST00000222254.13	NP_005018.2	O00459
PIK3R2	NR_073517.2 link	n.1492T>C		non_coding_transcript_exon_variant	Exon 8 of 16
PIK3R2	NR_162071.1 link	n.1275T>C		non_coding_transcript_exon_variant	Exon 7 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R2	ENST00000222254.13 link	c.937T>C	p.Ser313Pro	missense_variant	Exon 8 of 16	1	NM_005027.4	ENSP00000222254.6		O00459
ENSG00000268173	ENST00000593731.1 link	n.937T>C		non_coding_transcript_exon_variant	Exon 8 of 25	2		ENSP00000471914.1

Frequencies

GnomAD3 genomes

AF:

0.955

AC:

145316

AN:

152116

Hom.:

69429

Cov.:

show subpopulations

Gnomad AFR

AF:

0.967

Gnomad AMI

AF:

0.982

Gnomad AMR

AF:

0.963

Gnomad ASJ

AF:

0.950

Gnomad EAS

AF:

0.965

Gnomad SAS

AF:

0.921

Gnomad FIN

AF:

0.956

Gnomad MID

AF:

0.937

Gnomad NFE

AF:

0.948

Gnomad OTH

AF:

0.959

GnomAD2 exomes

AF:

0.952

AC:

234355

AN:

246170

AF XY:

0.949

show subpopulations

Gnomad AFR exome

AF:

0.968

Gnomad AMR exome

AF:

0.973

Gnomad ASJ exome

AF:

0.947

Gnomad EAS exome

AF:

0.967

Gnomad FIN exome

AF:

0.953

Gnomad NFE exome

AF:

0.949

Gnomad OTH exome

AF:

0.946

GnomAD4 exome

AF:

0.949

AC:

1375848

AN:

1449220

Hom.:

653454

Cov.:

AF XY:

0.948

AC XY:

683561

AN XY:

720998

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.965

AC:

32115

AN:

33272

American (AMR)

AF:

0.971

AC:

43254

AN:

44548

Ashkenazi Jewish (ASJ)

AF:

0.949

AC:

24625

AN:

25958

East Asian (EAS)

AF:

0.963

AC:

38142

AN:

39598

South Asian (SAS)

AF:

0.919

AC:

78896

AN:

85820

European-Finnish (FIN)

AF:

0.952

AC:

50510

AN:

53078

Middle Eastern (MID)

AF:

0.908

AC:

5172

AN:

5698

European-Non Finnish (NFE)

AF:

0.950

AC:

1046196

AN:

1101332

Other (OTH)

AF:

0.950

AC:

56938

AN:

59916

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.394

Heterozygous variant carriers

3237

6474

9710

12947

16184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.955

AC:

145437

AN:

152234

Hom.:

69490

Cov.:

AF XY:

0.955

AC XY:

71075

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.967

AC:

40197

AN:

41554

American (AMR)

AF:

0.963

AC:

14711

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.950

AC:

3298

AN:

3472

East Asian (EAS)

AF:

0.965

AC:

4985

AN:

5166

South Asian (SAS)

AF:

0.921

AC:

4447

AN:

4826

European-Finnish (FIN)

AF:

0.956

AC:

10150

AN:

10618

Middle Eastern (MID)

AF:

0.935

AC:

275

AN:

294

European-Non Finnish (NFE)

AF:

0.948

AC:

64453

AN:

68000

Other (OTH)

AF:

0.960

AC:

2025

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

349

699

1048

1398

1747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.950

Hom.:

144665

Bravo

AF:

0.957

TwinsUK

AF:

0.947

AC:

3512

ALSPAC

AF:

0.954

AC:

3677

ESP6500AA

AF:

0.969

AC:

4267

ESP6500EA

AF:

0.948

AC:

8150

ExAC

AF:

0.949

AC:

115094

Asia WGS

AF:

0.943

AC:

3279

AN:

3478

EpiCase

AF:

0.949

EpiControl

AF:

0.946

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1

Benign:3

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.5

(source)

DANN

Benign

0.067

DEOGEN2

Benign

0.12

T;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0042

LIST_S2

Benign

0.052

.;T;.

MetaRNN

Benign

0.0000011

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

N;.;N

PhyloP100

0.0020

PrimateAI

Benign

0.40

PROVEAN

Benign

1.7

N;.;.

REVEL

Benign

0.024

Sift

Benign

0.72

T;.;.

Sift4G

Benign

0.54

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.028

MPC

0.35

ClinPred

0.00060

GERP RS

-2.0

Varity_R

0.038

gMVP

0.33

Mutation Taster

=67/33

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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chr19-18162237-T-C

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