NM_005027.4:c.34C>G

Variant names:

• chr19-18155913-C-G
• rs1308748759
• NM_005027.4:c.34C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005027.4(PIK3R2):​c.34C>G​(p.Leu12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,412,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L12L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14850998).

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.34C>G	p.Leu12Val	missense	Exon 2 of 16	NP_005018.2	O00459
	PIK3R2	NR_073517.2		n.589C>G		non_coding_transcript_exon	Exon 2 of 16
	PIK3R2	NR_162071.1		n.589C>G		non_coding_transcript_exon	Exon 2 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R2	ENST00000222254.13	TSL:1 MANE Select	c.34C>G	p.Leu12Val	missense	Exon 2 of 16	ENSP00000222254.6	O00459
	ENSG00000268173	ENST00000593731.1	TSL:2	n.34C>G		non_coding_transcript_exon	Exon 2 of 25	ENSP00000471914.1
	PIK3R2	ENST00000617130.6	TSL:1	n.34C>G		non_coding_transcript_exon	Exon 2 of 15	ENSP00000477864.2	A0A7I2U3A3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 169556 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1412628 Hom.: 0 Cov.: 31 AF XY: 0.00000286 AC XY: 2 AN XY: 698462

African (AFR) AF: 0.00 AC: 0 AN: 32098

American (AMR) AF: 0.00 AC: 0 AN: 38020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25258

East Asian (EAS) AF: 0.0000272 AC: 1 AN: 36802

South Asian (SAS) AF: 0.00 AC: 0 AN: 80564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1087104

Other (OTH) AF: 0.00 AC: 0 AN: 58504

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.056
Sift	Benign	0.10	T
Sift4G	Uncertain	0.045	D
Polyphen		0.0030	B
Vest4		0.20
MutPred		0.26		Loss of sheet (P = 0.1158)
MVP		0.26
MPC		0.29
ClinPred		0.38	T
GERP RS		0.80
Varity_R		0.14
gMVP		0.45
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs1308748759; hg19: chr19-18266723; COSMIC: COSV53221231;