Genetic Variant PIK3R2:p.Pro615Pro (chr19-18168762-G-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_005027.4(PIK3R2):c.1845G>A(p.Pro615Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,549,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. P615P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

PIK3R2
NM_005027.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.720

Publications

2 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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 19-18168762-G-A is Benign according to our data. Variant chr19-18168762-G-A is described in ClinVar as Benign. ClinVar VariationId is 772601.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.72 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000741 (11/148542) while in subpopulation AMR AF = 0.000267 (4/14976). AF 95% confidence interval is 0.000091. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 11 AD gene.

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
PIK3R2	NM_005027.4	MANE Select	c.1845G>A	p.Pro615Pro	synonymous	Exon 15 of 16	NP_005018.2
PIK3R2	NR_073517.2		n.2449G>A		non_coding_transcript_exon	Exon 15 of 16
PIK3R2	NR_162071.1		n.2187G>A		non_coding_transcript_exon	Exon 14 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIK3R2	ENST00000222254.13	TSL:1 MANE Select	c.1845G>A	p.Pro615Pro	synonymous	Exon 15 of 16	ENSP00000222254.6
ENSG00000268173	ENST00000593731.1	TSL:2	n.1845G>A		non_coding_transcript_exon	Exon 15 of 25	ENSP00000471914.1
PIK3R2	ENST00000617130.6	TSL:1	n.*873G>A		non_coding_transcript_exon	Exon 14 of 15	ENSP00000477864.2

Frequencies

GnomAD3 genomes

AF:

0.0000741

AC:

AN:

148408

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000267

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000214

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000596

Gnomad OTH

AF:

0.000486

GnomAD2 exomes

AF:

0.000493

AC:

121

AN:

245434

AF XY:

0.000293

show subpopulations

Gnomad AFR exome

AF:

0.0000626

Gnomad AMR exome

AF:

0.00293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000600

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000552

Gnomad OTH exome

AF:

0.000334

GnomAD4 exome

AF:

0.000144

AC:

202

AN:

1400482

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

697016

show subpopulations

African (AFR)

AF:

0.0000631

AC:

AN:

31680

American (AMR)

AF:

0.00263

AC:

113

AN:

43044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23844

East Asian (EAS)

AF:

0.000509

AC:

AN:

35346

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46742

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5516

European-Non Finnish (NFE)

AF:

0.0000578

AC:

AN:

1072420

Other (OTH)

AF:

0.000107

AC:

AN:

56216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000741

AC:

AN:

148542

Hom.:

Cov.:

AF XY:

0.0000689

AC XY:

AN XY:

72596

show subpopulations

African (AFR)

AF:

0.0000245

AC:

AN:

40870

American (AMR)

AF:

0.000267

AC:

AN:

14976

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3434

East Asian (EAS)

AF:

0.000214

AC:

AN:

4672

South Asian (SAS)

AF:

0.00

AC:

AN:

4350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9912

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000596

AC:

AN:

67066

Other (OTH)

AF:

0.000481

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.000181

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

PIK3R2-related disorder

Benign:1

Jan 27, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

-0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over