19-18161401-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005027.4(PIK3R2):c.721C>T(p.Pro241Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000935 in 1,070,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P241T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 9.3e-7 ( 0 hom. )

Consequence

PIK3R2
NM_005027.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.983

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09442276).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PIK3R2	NM_005027.4 link	c.721C>T	p.Pro241Ser	missense_variant	Exon 6 of 16	ENST00000222254.13	NP_005018.2
PIK3R2	NR_073517.2 link	n.1276C>T		non_coding_transcript_exon_variant	Exon 6 of 16
PIK3R2	NR_162071.1 link	n.1153+216C>T		intron_variant	Intron 5 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R2	ENST00000222254.13 link	c.721C>T	p.Pro241Ser	missense_variant	Exon 6 of 16	1	NM_005027.4	ENSP00000222254.6
ENSG00000268173	ENST00000593731.1 link	n.721C>T		non_coding_transcript_exon_variant	Exon 6 of 25	2		ENSP00000471914.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

4564

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.35e-7

AC:

AN:

1070008

Hom.:

Cov.:

AF XY:

0.00000196

AC XY:

AN XY:

509280

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

21564

American (AMR)

AF:

0.00

AC:

AN:

8062

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13118

East Asian (EAS)

AF:

0.00

AC:

AN:

23088

South Asian (SAS)

AF:

0.00

AC:

AN:

23892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2796

European-Non Finnish (NFE)

AF:

0.00000109

AC:

AN:

914492

Other (OTH)

AF:

0.00

AC:

AN:

41834

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.059

T;T;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.63

.;T;.

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.094

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;N

PhyloP100

0.98

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.28

N;.;.

REVEL

Benign

0.039

Sift

Benign

0.17

T;.;.

Sift4G

Benign

0.19

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.015

MutPred

0.52

Gain of MoRF binding (P = 0.0311);Gain of MoRF binding (P = 0.0311);Gain of MoRF binding (P = 0.0311);

MVP

0.082

MPC

0.29

ClinPred

0.13

GERP RS

0.76

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.094

gMVP

0.53

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over