19-18161401-C-A

Position:

• chr19-18161401-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005027.4(PIK3R2):​c.721C>A​(p.Pro241Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,070,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.983

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07839826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3R2	NM_005027.4	c.721C>A	p.Pro241Thr	missense_variant	6/16	ENST00000222254.13	NP_005018.2
PIK3R2	NR_073517.2	n.1276C>A		non_coding_transcript_exon_variant	6/16
PIK3R2	NR_162071.1	n.1153+216C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3R2	ENST00000222254.13	c.721C>A	p.Pro241Thr	missense_variant	6/16	1	NM_005027.4	ENSP00000222254.6
ENSG00000268173	ENST00000593731.1	n.721C>A		non_coding_transcript_exon_variant	6/25	2		ENSP00000471914.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000187 AC: 2 AN: 1070004 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 509276

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000109

Gnomad4 OTH exome AF: 0.0000239

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 01, 2019

This sequence change replaces proline with threonine at codon 241 of the PIK3R2 protein (p.Pro241Thr). The proline residue is weakly conserved and there is a small physicochemical difference between proline and threonine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with PIK3R2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.069	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.61	.;T;.
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.25	N;.;.
REVEL	Benign	0.039
Sift	Benign	0.28	T;.;.
Sift4G	Benign	0.25	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.038
MutPred		0.50		Gain of phosphorylation at P241 (P = 0.0245);Gain of phosphorylation at P241 (P = 0.0245);Gain of phosphorylation at P241 (P = 0.0245);
MVP		0.082
MPC		0.31
ClinPred		0.16	T
GERP RS		0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1168878327; hg19: chr19-18272211;