rs201370957

chr19-18156039-G-Achr19-18156039-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005027.4(PIK3R2):c.160G>A(p.Val54Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00379 in 1,561,330 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (16 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:7
• Conservation: PhyloP100: 2.60

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0098333955).
• BP6: Variant 19-18156039-G-A is Benign according to our data. Variant chr19-18156039-G-A is described in ClinVar as [Benign]. Clinvar id is 468317.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-18156039-G-A is described in Lovd as [Benign]. Variant chr19-18156039-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0023 (351/152360) while in subpopulation NFE AF= 0.0042 (286/68026). AF 95% confidence interval is 0.0038. There are 2 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 351 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R2	NM_005027.4	c.160G>A	p.Val54Met	missense_variant	2/16	ENST00000222254.13
PIK3R2	NR_073517.2	n.715G>A		non_coding_transcript_exon_variant	2/16
PIK3R2	NR_162071.1	n.715G>A		non_coding_transcript_exon_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R2	ENST00000222254.13	c.160G>A	p.Val54Met	missense_variant	2/16	1	NM_005027.4	P1
PIK3R2	ENST00000617130.5	c.160G>A	p.Val54Met	missense_variant, NMD_transcript_variant	2/15	1
PIK3R2	ENST00000426902.5	c.160G>A	p.Val54Met	missense_variant, NMD_transcript_variant	1/15	2
PIK3R2	ENST00000617642.2	c.160G>A	p.Val54Met	missense_variant, NMD_transcript_variant	2/14	5

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 351 AN: 152246 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00420

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00203 AC: 328 AN: 161974 Hom.: 1 AF XY: 0.00215 AC XY: 190 AN XY: 88192

Gnomad AFR exome AF: 0.000722

Gnomad AMR exome AF: 0.000613

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000423

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00435

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.00395 AC: 5559 AN: 1408970 Hom.: 16 Cov.: 31 AF XY: 0.00384 AC XY: 2673 AN XY: 696366

Gnomad4 AFR exome AF: 0.000438

Gnomad4 AMR exome AF: 0.000590

Gnomad4 ASJ exome AF: 0.0000795

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000498

Gnomad4 FIN exome AF: 0.00155

Gnomad4 NFE exome AF: 0.00489

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.00230 AC: 351 AN: 152360 Hom.: 2 Cov.: 32 AF XY: 0.00238 AC XY: 177 AN XY: 74500

Gnomad4 AFR AF: 0.000793

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00103

Gnomad4 NFE AF: 0.00420

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00334 Hom.: 2

Bravo AF: 0.00220

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00118 AC: 5

ESP6500EA AF: 0.00411 AC: 34

ExAC AF: 0.00164 AC: 188

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PIK3R2: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes Benign:1

Benign, reviewed by expert panel

curation

ClinGen Brain Malformations Variant Curation Expert Panel

Feb 11, 2022

The c.160G>A (NM_005027.4) variant in PIK3R2 is a missense variant predicted to cause substitution of (p.Val54Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.004092 in the European (non Finnish) population, which is higher than the ClinGen BMEP threshold ([>=0.00185]) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: BA1; -8 points (VCEP specifications version 1; Approved: 1/31/2021) -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

PIK3R2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2021

This variant is classified as 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;T
Eigen	Benign	-0.0035
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.65	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0098	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;N
MutationTaster	Benign	0.88	N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.61	N;.;.
REVEL	Benign	0.059
Sift	Uncertain	0.011	D;.;.
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.98	D;.;D
Vest4		0.27
MVP		0.29
MPC		0.34
ClinPred		0.014	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs201370957; hg19: chr19-18266849; COSMIC: COSV105838506; COSMIC: COSV105838506;