19-18167213-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.1643C>T(p.Ala548Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000949 in 1,611,792 control chromosomes in the GnomAD database, including 9 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00081 (7 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.90

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=0.0069634914).
• BP6: Variant 19-18167213-C-T is Benign according to our data. Variant chr19-18167213-C-T is described in ClinVar as [Benign]. Clinvar id is 468318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00226 (344/152256) while in subpopulation AFR AF= 0.00585 (243/41556). AF 95% confidence interval is 0.00524. There are 2 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 343 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R2	NM_005027.4	c.1643C>T	p.Ala548Val	missense_variant	13/16	ENST00000222254.13
PIK3R2	NR_073517.2	n.2247C>T		non_coding_transcript_exon_variant	13/16
PIK3R2	NR_162071.1	n.1981C>T		non_coding_transcript_exon_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R2	ENST00000222254.13	c.1643C>T	p.Ala548Val	missense_variant	13/16	1	NM_005027.4	P1

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 343 AN: 152138 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00584

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00138 AC: 342 AN: 248238 Hom.: 2 AF XY: 0.00119 AC XY: 160 AN XY: 134266

Gnomad AFR exome AF: 0.00507

Gnomad AMR exome AF: 0.00158

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000665

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000417

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.000812 AC: 1185 AN: 1459536 Hom.: 7 Cov.: 31 AF XY: 0.000763 AC XY: 554 AN XY: 726066

Gnomad4 AFR exome AF: 0.00637

Gnomad4 AMR exome AF: 0.00178

Gnomad4 ASJ exome AF: 0.0141

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000467

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000346

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152256 Hom.: 2 Cov.: 31 AF XY: 0.00205 AC XY: 153 AN XY: 74460

Gnomad4 AFR AF: 0.00585

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00155 Hom.: 0

Bravo AF: 0.00287

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00138 AC: 168

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000877

EpiControl AF: 0.000775

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	PIK3R2: BS1, BS2 -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.58	D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.0070	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.030
Sift	Benign	0.19	T;.
Sift4G	Benign	0.26	T;T
Polyphen		0.0	B;B
Vest4		0.12
MVP		0.23
MPC		0.83
ClinPred		0.0061	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066
gMVP		0.12

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: rs10413655; hg19: chr19-18278023; COSMIC: COSV55849659; COSMIC: COSV55849659;