rs2241088

chr19-18161380-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005027.4(PIK3R2):c.700A>C(p.Ser234Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.929 in 1,241,468 control chromosomes in the GnomAD database, including 536,112 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (65204 hom., cov: 32)
  • Exomes 𝑓: 0.93 (470908 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.29

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=5.7992236E-7).
• BP6: Variant 19-18161380-A-C is Benign according to our data. Variant chr19-18161380-A-C is described in ClinVar as [Benign]. Clinvar id is 497079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18161380-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R2	NM_005027.4	c.700A>C	p.Ser234Arg	missense_variant	6/16	ENST00000222254.13
PIK3R2	NR_073517.2	n.1255A>C		non_coding_transcript_exon_variant	6/16
PIK3R2	NR_162071.1	n.1153+195A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R2	ENST00000222254.13	c.700A>C	p.Ser234Arg	missense_variant	6/16	1	NM_005027.4	P1

Frequencies

GnomAD3 genomes AF: 0.932 AC: 139727 AN: 149952 Hom.: 65157 Cov.: 32

Gnomad AFR AF: 0.971

Gnomad AMI AF: 0.982

Gnomad AMR AF: 0.892

Gnomad ASJ AF: 0.931

Gnomad EAS AF: 0.910

Gnomad SAS AF: 0.877

Gnomad FIN AF: 0.875

Gnomad MID AF: 0.939

Gnomad NFE AF: 0.930

Gnomad OTH AF: 0.938

GnomAD3 exomes AF: 0.885 AC: 8559 AN: 9668 Hom.: 3833 AF XY: 0.885 AC XY: 5548 AN XY: 6266

Gnomad AFR exome AF: 0.968

Gnomad AMR exome AF: 0.873

Gnomad ASJ exome AF: 0.891

Gnomad EAS exome AF: 0.833

Gnomad SAS exome AF: 0.853

Gnomad FIN exome AF: 0.855

Gnomad NFE exome AF: 0.915

Gnomad OTH exome AF: 0.902

GnomAD4 exome AF: 0.929 AC: 1013468 AN: 1091408 Hom.: 470908 Cov.: 43 AF XY: 0.928 AC XY: 482883 AN XY: 520302

Gnomad4 AFR exome AF: 0.971

Gnomad4 AMR exome AF: 0.887

Gnomad4 ASJ exome AF: 0.924

Gnomad4 EAS exome AF: 0.928

Gnomad4 SAS exome AF: 0.867

Gnomad4 FIN exome AF: 0.884

Gnomad4 NFE exome AF: 0.931

Gnomad4 OTH exome AF: 0.927

GnomAD4 genome AF: 0.932 AC: 139827 AN: 150060 Hom.: 65204 Cov.: 32 AF XY: 0.926 AC XY: 67862 AN XY: 73274

Gnomad4 AFR AF: 0.971

Gnomad4 AMR AF: 0.892

Gnomad4 ASJ AF: 0.931

Gnomad4 EAS AF: 0.910

Gnomad4 SAS AF: 0.878

Gnomad4 FIN AF: 0.875

Gnomad4 NFE AF: 0.930

Gnomad4 OTH AF: 0.936

Alfa AF: 0.935 Hom.: 8248

Bravo AF: 0.937

TwinsUK AF: 0.940 AC: 3484

ALSPAC AF: 0.943 AC: 3635

ExAC AF: 0.826 AC: 6407

Asia WGS AF: 0.886 AC: 2787 AN: 3146

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.068	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.0018	N
MetaRNN	Benign	5.8e-7	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.29	N;.;N
MutationTaster	Benign	1.0	P
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.82	N;.;.
REVEL	Benign	0.0090
Sift	Benign	0.32	T;.;.
Sift4G	Benign	0.39	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.028
MutPred		0.32		Gain of MoRF binding (P = 0.0219);Gain of MoRF binding (P = 0.0219);Gain of MoRF binding (P = 0.0219);
MPC		0.31
ClinPred		0.0014	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.060
gMVP		0.29

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: rs2241088; hg19: chr19-18272190; COSMIC: COSV55848697; COSMIC: COSV55848697;