Genetic Variant PIK3R2:p.Pro721Pro (chr19-18169270-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005027.4(PIK3R2):c.2163C>T(p.Pro721Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00619 in 1,518,744 control chromosomes in the GnomAD database, including 273 homozygotes. 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. P721P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.010 ( 58 hom., cov: 33)

Exomes 𝑓: 0.0057 ( 215 hom. )

Consequence

PIK3R2
NM_005027.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.47

Publications

3 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 19-18169270-C-T is Benign according to our data. Variant chr19-18169270-C-T is described in ClinVar as Benign. ClinVar VariationId is 468322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.47 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0584 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.2163C>T	p.Pro721Pro	synonymous	Exon 16 of 16	NP_005018.2	O00459
PIK3R2	NR_073517.2		n.2767C>T		non_coding_transcript_exon	Exon 16 of 16
PIK3R2	NR_162071.1		n.2505C>T		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.2163C>T	p.Pro721Pro	synonymous	Exon 16 of 16	ENSP00000222254.6	O00459
ENSG00000268173	ENST00000593731.1	TSL:2	n.2163C>T		non_coding_transcript_exon	Exon 16 of 25	ENSP00000471914.1
PIK3R2	ENST00000617130.6	TSL:1	n.*1191C>T		non_coding_transcript_exon	Exon 15 of 15	ENSP00000477864.2	A0A7I2U3A3

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1551

AN:

151834

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0612

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.0538

Gnomad SAS

AF:

0.0408

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000707

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.0259

AC:

3092

AN:

119476

AF XY:

0.0250

show subpopulations

Gnomad AFR exome

AF:

0.00134

Gnomad AMR exome

AF:

0.0742

Gnomad ASJ exome

AF:

0.00220

Gnomad EAS exome

AF:

0.0617

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000839

Gnomad OTH exome

AF:

0.0131

GnomAD4 exome

AF:

0.00573

AC:

7834

AN:

1366802

Hom.:

215

Cov.:

AF XY:

0.00652

AC XY:

4402

AN XY:

674942

show subpopulations

African (AFR)

AF:

0.00126

AC:

AN:

30108

American (AMR)

AF:

0.0695

AC:

2267

AN:

32606

Ashkenazi Jewish (ASJ)

AF:

0.00177

AC:

AN:

24228

East Asian (EAS)

AF:

0.0365

AC:

1265

AN:

34632

South Asian (SAS)

AF:

0.0367

AC:

2866

AN:

78074

European-Finnish (FIN)

AF:

0.0000295

AC:

AN:

33930

Middle Eastern (MID)

AF:

0.00149

AC:

AN:

4016

European-Non Finnish (NFE)

AF:

0.000770

AC:

826

AN:

1072342

Other (OTH)

AF:

0.00918

AC:

522

AN:

56866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

Heterozygous variant carriers

390

780

1169

1559

1949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.0103

AC:

1563

AN:

151942

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

925

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41514

American (AMR)

AF:

0.0617

AC:

941

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3468

East Asian (EAS)

AF:

0.0538

AC:

278

AN:

5166

South Asian (SAS)

AF:

0.0406

AC:

196

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000707

AC:

AN:

67906

Other (OTH)

AF:

0.0166

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

154

232

309

386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00148

Hom.:

Bravo

AF:

0.0131

Asia WGS

AF:

0.0500

AC:

173

AN:

3460

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

0.87

(source)

DANN

Uncertain

0.98

PhyloP100

-1.5

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