19-18162237-T-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.937T>C(p.Ser313Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.95 in 1,601,454 control chromosomes in the GnomAD database, including 722,944 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S313A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.96 (69490 hom., cov: 32)
  • Exomes 𝑓: 0.95 (653454 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00200

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=1.0996432E-6).
• BP6: Variant 19-18162237-T-C is Benign according to our data. Variant chr19-18162237-T-C is described in ClinVar as [Benign]. Clinvar id is 803546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18162237-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R2	NM_005027.4	c.937T>C	p.Ser313Pro	missense_variant	8/16	ENST00000222254.13
PIK3R2	NR_073517.2	n.1492T>C		non_coding_transcript_exon_variant	8/16
PIK3R2	NR_162071.1	n.1275T>C		non_coding_transcript_exon_variant	7/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R2	ENST00000222254.13	c.937T>C	p.Ser313Pro	missense_variant	8/16	1	NM_005027.4	P1

Frequencies

GnomAD3 genomes AF: 0.955 AC: 145316 AN: 152116 Hom.: 69429 Cov.: 32

Gnomad AFR AF: 0.967

Gnomad AMI AF: 0.982

Gnomad AMR AF: 0.963

Gnomad ASJ AF: 0.950

Gnomad EAS AF: 0.965

Gnomad SAS AF: 0.921

Gnomad FIN AF: 0.956

Gnomad MID AF: 0.937

Gnomad NFE AF: 0.948

Gnomad OTH AF: 0.959

GnomAD3 exomes AF: 0.952 AC: 234355 AN: 246170 Hom.: 111614 AF XY: 0.949 AC XY: 126784 AN XY: 133580

Gnomad AFR exome AF: 0.968

Gnomad AMR exome AF: 0.973

Gnomad ASJ exome AF: 0.947

Gnomad EAS exome AF: 0.967

Gnomad SAS exome AF: 0.922

Gnomad FIN exome AF: 0.953

Gnomad NFE exome AF: 0.949

Gnomad OTH exome AF: 0.946

GnomAD4 exome AF: 0.949 AC: 1375848 AN: 1449220 Hom.: 653454 Cov.: 37 AF XY: 0.948 AC XY: 683561 AN XY: 720998

Gnomad4 AFR exome AF: 0.965

Gnomad4 AMR exome AF: 0.971

Gnomad4 ASJ exome AF: 0.949

Gnomad4 EAS exome AF: 0.963

Gnomad4 SAS exome AF: 0.919

Gnomad4 FIN exome AF: 0.952

Gnomad4 NFE exome AF: 0.950

Gnomad4 OTH exome AF: 0.950

GnomAD4 genome AF: 0.955 AC: 145437 AN: 152234 Hom.: 69490 Cov.: 32 AF XY: 0.955 AC XY: 71075 AN XY: 74416

Gnomad4 AFR AF: 0.967

Gnomad4 AMR AF: 0.963

Gnomad4 ASJ AF: 0.950

Gnomad4 EAS AF: 0.965

Gnomad4 SAS AF: 0.921

Gnomad4 FIN AF: 0.956

Gnomad4 NFE AF: 0.948

Gnomad4 OTH AF: 0.960

Alfa AF: 0.950 Hom.: 102168

Bravo AF: 0.957

TwinsUK AF: 0.947 AC: 3512

ALSPAC AF: 0.954 AC: 3677

ESP6500AA AF: 0.969 AC: 4267

ESP6500EA AF: 0.948 AC: 8150

ExAC AF: 0.949 AC: 115094

Asia WGS AF: 0.943 AC: 3279 AN: 3478

EpiCase AF: 0.949

EpiControl AF: 0.946

ClinVar

Significance: Benign

Submissions summary: Benign:6

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	2.5
Dann	Benign	0.067
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0042	N
MetaRNN	Benign	0.0000011	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N;.;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.7	N;.;.
REVEL	Benign	0.024
Sift	Benign	0.72	T;.;.
Sift4G	Benign	0.54	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.028
MPC		0.35
ClinPred		0.00060	T
GERP RS		-2.0
Varity_R		0.038
gMVP		0.33

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: rs1011320; hg19: chr19-18273047;