rs28730848

Positions:

• chr19-18162203-G-A
• chr19-18162203-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005027.4(PIK3R2):​c.903G>A​(p.Ala301Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0496 in 1,547,836 control chromosomes in the GnomAD database, including 2,181 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (155 hom., cov: 33)
  • Exomes 𝑓: 0.051 (2026 hom.)
• Consequence: PIK3R2 NM_005027.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001386
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.40

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]

ENSG00000268173 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 19-18162203-G-A is Benign according to our data. Variant chr19-18162203-G-A is described in ClinVar as [Benign]. Clinvar id is 468326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18162203-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3R2	NM_005027.4	c.903G>A	p.Ala301Ala	splice_region_variant, synonymous_variant	8/16	ENST00000222254.13	NP_005018.2
PIK3R2	NR_073517.2	n.1458G>A		splice_region_variant, non_coding_transcript_exon_variant	8/16
PIK3R2	NR_162071.1	n.1241G>A		splice_region_variant, non_coding_transcript_exon_variant	7/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3R2	ENST00000222254.13	c.903G>A	p.Ala301Ala	splice_region_variant, synonymous_variant	8/16	1	NM_005027.4	ENSP00000222254.6
ENSG00000268173	ENST00000593731.1	n.903G>A		splice_region_variant, non_coding_transcript_exon_variant	8/25	2		ENSP00000471914.1

Frequencies

GnomAD3 genomes AF: 0.0378 AC: 5746 AN: 152128 Hom.: 154 Cov.: 33

Gnomad AFR AF: 0.00937

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.0579

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0663

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.0892

Gnomad NFE AF: 0.0572

Gnomad OTH AF: 0.0369

GnomAD3 exomes AF: 0.0430 AC: 10290 AN: 239038 Hom.: 288 AF XY: 0.0460 AC XY: 5970 AN XY: 129674

Gnomad AFR exome AF: 0.00778

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.0489

Gnomad EAS exome AF: 0.000328

Gnomad SAS exome AF: 0.0659

Gnomad FIN exome AF: 0.0385

Gnomad NFE exome AF: 0.0572

Gnomad OTH exome AF: 0.0465

GnomAD4 exome AF: 0.0509 AC: 71041 AN: 1395590 Hom.: 2026 Cov.: 28 AF XY: 0.0521 AC XY: 36264 AN XY: 695802

Gnomad4 AFR exome AF: 0.00818

Gnomad4 AMR exome AF: 0.0191

Gnomad4 ASJ exome AF: 0.0487

Gnomad4 EAS exome AF: 0.000178

Gnomad4 SAS exome AF: 0.0682

Gnomad4 FIN exome AF: 0.0393

Gnomad4 NFE exome AF: 0.0549

Gnomad4 OTH exome AF: 0.0472

GnomAD4 genome AF: 0.0377 AC: 5745 AN: 152246 Hom.: 155 Cov.: 33 AF XY: 0.0369 AC XY: 2744 AN XY: 74422

Gnomad4 AFR AF: 0.00934

Gnomad4 AMR AF: 0.0226

Gnomad4 ASJ AF: 0.0579

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0667

Gnomad4 FIN AF: 0.0395

Gnomad4 NFE AF: 0.0572

Gnomad4 OTH AF: 0.0366

Alfa AF: 0.0486 Hom.: 291

Bravo AF: 0.0344

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.4
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0060
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: rs28730848; hg19: chr19-18273013; COSMIC: COSV55848943; COSMIC: COSV55848943;