rs1168878327

Variant names:

• chr19-18161401-C-A
• rs1168878327
• NM_005027.4:c.721C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-18161401-C-A
• chr19-18161401-C-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.721C>A​(p.Pro241Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,070,004 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 (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.983
• 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=0.07839826).

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.721C>A	p.Pro241Thr	missense	Exon 6 of 16	NP_005018.2	O00459
	PIK3R2	NR_073517.2		n.1276C>A		non_coding_transcript_exon	Exon 6 of 16
	PIK3R2	NR_162071.1		n.1153+216C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R2	ENST00000222254.13	TSL:1 MANE Select	c.721C>A	p.Pro241Thr	missense	Exon 6 of 16	ENSP00000222254.6	O00459
	ENSG00000268173	ENST00000593731.1	TSL:2	n.721C>A		non_coding_transcript_exon	Exon 6 of 25	ENSP00000471914.1
	PIK3R2	ENST00000617130.6	TSL:1	n.598+216C>A		intron	N/A	ENSP00000477864.2	A0A7I2U3A3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 4564 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: 0.00000187 AC: 2 AN: 1070004 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 509276

African (AFR) AF: 0.00 AC: 0 AN: 21564

American (AMR) AF: 0.00 AC: 0 AN: 8062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13118

East Asian (EAS) AF: 0.00 AC: 0 AN: 23088

South Asian (SAS) AF: 0.00 AC: 0 AN: 23888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2796

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 914492

Other (OTH) AF: 0.0000239 AC: 1 AN: 41834

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.98
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.25	N
REVEL	Benign	0.039
Sift	Benign	0.28	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.038
MutPred		0.50		Gain of phosphorylation at P241 (P = 0.0245)
MVP		0.082
MPC		0.31
ClinPred		0.16	T
GERP RS		0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.45
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1168878327; hg19: chr19-18272211;