19-18169286-G-A

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.2179G>A(p.Ala727Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 1,495,138 control chromosomes in the GnomAD database, including 1,847 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 151 hom., cov: 33)

Exomes 𝑓: 0.045 ( 1696 hom. )

Consequence

PIK3R2
NM_005027.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0820

Publications

9 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: G2P, Labcorp Genetics (formerly Invitae), Illumina, 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=0.0014354289).

BP6

Variant 19-18169286-G-A is Benign according to our data. Variant chr19-18169286-G-A is described in ClinVar as Benign. ClinVar VariationId is 468323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005027.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIK3R2	NM_005027.4	MANE Select	c.2179G>A	p.Ala727Thr	missense	Exon 16 of 16	NP_005018.2	O00459
PIK3R2	NR_073517.2		n.2783G>A		non_coding_transcript_exon	Exon 16 of 16
PIK3R2	NR_162071.1		n.2521G>A		non_coding_transcript_exon	Exon 15 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIK3R2	ENST00000222254.13	TSL:1 MANE Select	c.2179G>A	p.Ala727Thr	missense	Exon 16 of 16	ENSP00000222254.6	O00459
ENSG00000268173	ENST00000593731.1	TSL:2	n.2179G>A		non_coding_transcript_exon	Exon 16 of 25	ENSP00000471914.1
PIK3R2	ENST00000617130.6	TSL:1	n.*1207G>A		non_coding_transcript_exon	Exon 15 of 15	ENSP00000477864.2	A0A7I2U3A3

Frequencies

GnomAD3 genomes

AF:

0.0383

AC:

5819

AN:

151832

Hom.:

151

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00918

Gnomad AMI

AF:

0.0308

Gnomad AMR

AF:

0.0437

Gnomad ASJ

AF:

0.0828

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.0855

Gnomad MID

AF:

0.0446

Gnomad NFE

AF:

0.0502

Gnomad OTH

AF:

0.0422

GnomAD2 exomes

AF:

0.0420

AC:

4305

AN:

102418

AF XY:

0.0411

show subpopulations

Gnomad AFR exome

AF:

0.00954

Gnomad AMR exome

AF:

0.0355

Gnomad ASJ exome

AF:

0.101

Gnomad EAS exome

AF:

0.000344

Gnomad FIN exome

AF:

0.0779

Gnomad NFE exome

AF:

0.0573

Gnomad OTH exome

AF:

0.0508

GnomAD4 exome

AF:

0.0451

AC:

60598

AN:

1343198

Hom.:

1696

Cov.:

AF XY:

0.0446

AC XY:

29493

AN XY:

661842

show subpopulations

African (AFR)

AF:

0.00765

AC:

224

AN:

29284

American (AMR)

AF:

0.0348

AC:

1038

AN:

29796

Ashkenazi Jewish (ASJ)

AF:

0.0936

AC:

2153

AN:

23012

East Asian (EAS)

AF:

0.000118

AC:

AN:

33878

South Asian (SAS)

AF:

0.0125

AC:

928

AN:

74368

European-Finnish (FIN)

AF:

0.0714

AC:

2354

AN:

32982

Middle Eastern (MID)

AF:

0.0622

AC:

243

AN:

3906

European-Non Finnish (NFE)

AF:

0.0481

AC:

51048

AN:

1060322

Other (OTH)

AF:

0.0468

AC:

2606

AN:

55650

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

2681

5362

8043

10724

13405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1912

3824

5736

7648

9560

<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:

0.0383

AC:

5818

AN:

151940

Hom.:

151

Cov.:

AF XY:

0.0400

AC XY:

2974

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.00915

AC:

380

AN:

41508

American (AMR)

AF:

0.0436

AC:

666

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.0828

AC:

287

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.0101

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0855

AC:

896

AN:

10480

Middle Eastern (MID)

AF:

0.0445

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0502

AC:

3411

AN:

67902

Other (OTH)

AF:

0.0418

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

291

582

872

1163

1454

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0473

Hom.:

Bravo

AF:

0.0341

TwinsUK

AF:

0.0434

AC:

161

ALSPAC

AF:

0.0467

AC:

180

ESP6500AA

AF:

0.0110

AC:

ESP6500EA

AF:

0.0472

AC:

210

ExAC

AF:

0.0282

AC:

1734

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (3)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.029

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.082

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.71

REVEL

Benign

0.042

Sift

Pathogenic

0.0

Sift4G

Benign

0.21

Polyphen

0.0

Vest4

0.050

MPC

0.80

ClinPred

0.021

GERP RS

-2.8

Varity_R

0.16

gMVP

0.12

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over