19-18155889-C-T

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.10C>T(p.Pro4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,552,084 control chromosomes in the GnomAD database, including 22 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (17 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.193

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=0.0012272596).
• BP6: Variant 19-18155889-C-T is Benign according to our data. Variant chr19-18155889-C-T is described in ClinVar as [Benign]. Clinvar id is 707439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00116 (177/152332) while in subpopulation EAS AF= 0.0311 (161/5178). AF 95% confidence interval is 0.0272. There are 5 homozygotes in gnomad4. There are 93 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 177 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R2	NM_005027.4	c.10C>T	p.Pro4Ser	missense_variant	2/16	ENST00000222254.13
PIK3R2	NR_073517.2	n.565C>T		non_coding_transcript_exon_variant	2/16
PIK3R2	NR_162071.1	n.565C>T		non_coding_transcript_exon_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R2	ENST00000222254.13	c.10C>T	p.Pro4Ser	missense_variant	2/16	1	NM_005027.4	P1
PIK3R2	ENST00000617130.5	c.10C>T	p.Pro4Ser	missense_variant, NMD_transcript_variant	2/15	1
PIK3R2	ENST00000426902.5	c.10C>T	p.Pro4Ser	missense_variant, NMD_transcript_variant	1/15	2
PIK3R2	ENST00000617642.2	c.10C>T	p.Pro4Ser	missense_variant, NMD_transcript_variant	2/14	5

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152214 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0310

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00246 AC: 380 AN: 154756 Hom.: 4 AF XY: 0.00231 AC XY: 193 AN XY: 83434

Gnomad AFR exome AF: 0.000139

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0306

Gnomad SAS exome AF: 0.000526

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.00185

GnomAD4 exome AF: 0.00101 AC: 1417 AN: 1399752 Hom.: 17 Cov.: 31 AF XY: 0.000991 AC XY: 685 AN XY: 691014

Gnomad4 AFR exome AF: 0.0000320

Gnomad4 AMR exome AF: 0.0000832

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0332

Gnomad4 SAS exome AF: 0.000491

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000352

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152332 Hom.: 5 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0311

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.00125

ExAC AF: 0.00196 AC: 214

Asia WGS AF: 0.0170 AC: 58 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 24, 2018

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	11
Dann	Benign	0.94
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.17	N
MetaRNN	Benign	0.0012	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.69	N;.;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.28	N;.;.
REVEL	Benign	0.014
Sift	Benign	0.23	T;.;.
Sift4G	Benign	0.44	T;T;T
Polyphen		0.0030	B;.;B
Vest4		0.054
MVP		0.15
MPC		0.28
ClinPred		0.0015	T
GERP RS		-0.45
Varity_R		0.10
gMVP		0.070

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: rs142933317; hg19: chr19-18266699; COSMIC: COSV53227621; COSMIC: COSV53227621;