19-18169286-G-T

Variant names:

• chr19-18169286-G-T
• rs149081991
• NM_005027.4:c.2179G>T

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.2179G>T​(p.Ala727Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,343,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A727T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0820
• Publications: 0 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=0.071751).

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.2179G>T	p.Ala727Ser	missense	Exon 16 of 16	NP_005018.2	O00459
	PIK3R2	NR_073517.2		n.2783G>T		non_coding_transcript_exon	Exon 16 of 16
	PIK3R2	NR_162071.1		n.2521G>T		non_coding_transcript_exon	Exon 15 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R2	ENST00000222254.13	TSL:1 MANE Select	c.2179G>T	p.Ala727Ser	missense	Exon 16 of 16	ENSP00000222254.6	O00459
	ENSG00000268173	ENST00000593731.1	TSL:2	n.2179G>T		non_coding_transcript_exon	Exon 16 of 25	ENSP00000471914.1
	PIK3R2	ENST00000617130.6	TSL:1	n.*1207G>T		non_coding_transcript_exon	Exon 15 of 15	ENSP00000477864.2	A0A7I2U3A3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1343396 Hom.: 0 Cov.: 31 AF XY: 0.00000151 AC XY: 1 AN XY: 661942

African (AFR) AF: 0.00 AC: 0 AN: 29284

American (AMR) AF: 0.00 AC: 0 AN: 29798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23016

East Asian (EAS) AF: 0.0000295 AC: 1 AN: 33878

South Asian (SAS) AF: 0.00 AC: 0 AN: 74368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3906

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060512

Other (OTH) AF: 0.00 AC: 0 AN: 55652

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.1
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.086	N
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.082
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.017
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.25	T
Polyphen		0.012	B
Vest4		0.13
MutPred		0.20		Gain of glycosylation at A727 (P = 0.0027)
MVP		0.23
MPC		0.76
ClinPred		0.093	T
GERP RS		-2.8
Varity_R		0.17
gMVP		0.12
Mutation Taster		=99/1	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: rs149081991; hg19: chr19-18280096;