rs1371555508

Variant names:

• chr19-18155908-G-A
• rs1371555508
• NM_005027.4:c.29G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-18155908-G-A
• chr19-18155908-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005027.4(PIK3R2):​c.29G>A​(p.Arg10His) variant causes a missense change. The variant allele was found at a frequency of 0.00000922 in 1,409,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000092 (0 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.60
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Illumina, G2P
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40843883).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

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.29G>A	p.Arg10His	missense	Exon 2 of 16	NP_005018.2	O00459
	PIK3R2	NR_073517.2		n.584G>A		non_coding_transcript_exon	Exon 2 of 16
	PIK3R2	NR_162071.1		n.584G>A		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.29G>A	p.Arg10His	missense	Exon 2 of 16	ENSP00000222254.6	O00459
	ENSG00000268173	ENST00000593731.1	TSL:2	n.29G>A		non_coding_transcript_exon	Exon 2 of 25	ENSP00000471914.1
	PIK3R2	ENST00000617130.6	TSL:1	n.29G>A		non_coding_transcript_exon	Exon 2 of 15	ENSP00000477864.2	A0A7I2U3A3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000603 AC: 1 AN: 165916 AF XY: 0.0000111

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: 0.00000922 AC: 13 AN: 1409720 Hom.: 0 Cov.: 31 AF XY: 0.0000100 AC XY: 7 AN XY: 696754

African (AFR) AF: 0.00 AC: 0 AN: 31934

American (AMR) AF: 0.00 AC: 0 AN: 37608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25210

East Asian (EAS) AF: 0.00 AC: 0 AN: 36630

South Asian (SAS) AF: 0.0000249 AC: 2 AN: 80346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.0000101 AC: 11 AN: 1085514

Other (OTH) AF: 0.00 AC: 0 AN: 58384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.55		Loss of disorder (P = 0.0714)
MVP		0.51
MPC		1.1
ClinPred		0.89	D
GERP RS		4.3
Varity_R		0.36
gMVP		0.65
Mutation Taster		=64/36	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: rs1371555508; hg19: chr19-18266718;