rs587776934

Variant names:

• chr19-18162974-G-A
• rs587776934
• NM_005027.4:c.1117G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-18162974-G-A
• chr19-18162974-G-C
• chr19-18162974-G-T

Variant summary

Our verdict is Pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1_Supporting PS4 PS2_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1117G>A (NM_005027.4) variant in PIK3R2 is a missense variant predicted to cause substitution of (p.Gly373Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides within the PIK3R2 SH2, sequence homology 2 domain of PIK3R2 that is defined as a critical functional domain by the ClinGen BMEP (PMID:26860062) (PM1_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; identified in 2 individuals with macrocephaly (>=2 SD) and Developmental Delay or Intellectual disability with cortical malformation, 13 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), it has been shown to significantly increase phosphorylation levels in patient cell lines (PMID:22729224), and has been identified in over 15 tumor samples in the literature and COSMIC (PMID:28086757,22729224, 28502725)). This variant has been identified as a de novo occurrence with confirmed parental relationships (PS2_moderate; PMID:22729224). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_P, PM1_P, PS4_VS, PS2_M; 13 points (VCEP specifications version 1; Approved: 1/31/2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA130573/MONDO:0016054/018

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:27 O:1
• Conservation: PhyloP100: 9.76
• Publications: 56 publications found

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]

PIK3R2 Gene-Disease associations (from GenCC):

• megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp
• overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000268173 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 8 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005027.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R2	NM_005027.4	MANE Select	c.1117G>A	p.Gly373Arg	missense	Exon 10 of 16	NP_005018.2	O00459
	PIK3R2	NR_073517.2		n.1672G>A		non_coding_transcript_exon	Exon 10 of 16
	PIK3R2	NR_162071.1		n.1455G>A		non_coding_transcript_exon	Exon 9 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R2	ENST00000222254.13	TSL:1 MANE Select	c.1117G>A	p.Gly373Arg	missense	Exon 10 of 16	ENSP00000222254.6	O00459
	ENSG00000268173	ENST00000593731.1	TSL:2	n.1117G>A		non_coding_transcript_exon	Exon 10 of 25	ENSP00000471914.1
	PIK3R2	ENST00000617130.6	TSL:1	n.*96G>A		non_coding_transcript_exon	Exon 9 of 15	ENSP00000477864.2	A0A7I2U3A3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461378 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726934

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111744

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
16	-	-	Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (17)
5	-	-	not provided (5)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)
1	-	-	Megalencephaly-capillary malformation-polymicrogyria syndrome (1)
1	-	-	Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes (1)
1	-	-	PIK3R2-related disorder (1)
1	-	-	Seizure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.089	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.69		Gain of MoRF binding (P = 0.0206)
MVP		0.84
MPC		2.1
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.78
Mutation Taster		=66/34	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587776934; hg19: chr19-18273784; COSMIC: COSV55846573; COSMIC: COSV55846573;