19-18155889-C-T

Variant names:

• chr19-18155889-C-T
• rs142933317
• NM_005027.4:c.10C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005027.4(PIK3R2):​c.10C>T​(p.Pro4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,552,084 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (17 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.193
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012272596).
• BP6: Variant 19-18155889-C-T is Benign according to our data. Variant chr19-18155889-C-T is described in ClinVar as Benign. ClinVar VariationId is 707439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00116 (177/152332) while in subpopulation EAS AF = 0.0311 (161/5178). AF 95% confidence interval is 0.0272. There are 5 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 177 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.10C>T	p.Pro4Ser	missense	Exon 2 of 16	NP_005018.2	O00459
	PIK3R2	NR_073517.2		n.565C>T		non_coding_transcript_exon	Exon 2 of 16
	PIK3R2	NR_162071.1		n.565C>T		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.10C>T	p.Pro4Ser	missense	Exon 2 of 16	ENSP00000222254.6	O00459
	ENSG00000268173	ENST00000593731.1	TSL:2	n.10C>T		non_coding_transcript_exon	Exon 2 of 25	ENSP00000471914.1
	PIK3R2	ENST00000617130.6	TSL:1	n.10C>T		non_coding_transcript_exon	Exon 2 of 15	ENSP00000477864.2	A0A7I2U3A3

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152214 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0310

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00246 AC: 380 AN: 154756 AF XY: 0.00231

Gnomad AFR exome AF: 0.000139

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0306

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.00185

GnomAD4 exome AF: 0.00101 AC: 1417 AN: 1399752 Hom.: 17 Cov.: 31 AF XY: 0.000991 AC XY: 685 AN XY: 691014

African (AFR) AF: 0.0000320 AC: 1 AN: 31248

American (AMR) AF: 0.0000832 AC: 3 AN: 36044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24944

East Asian (EAS) AF: 0.0332 AC: 1193 AN: 35920

South Asian (SAS) AF: 0.000491 AC: 39 AN: 79466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48138

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5686

European-Non Finnish (NFE) AF: 0.0000352 AC: 38 AN: 1080344

Other (OTH) AF: 0.00245 AC: 142 AN: 57962

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152332 Hom.: 5 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74488

African (AFR) AF: 0.00 AC: 0 AN: 41592

American (AMR) AF: 0.000261 AC: 4 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0311 AC: 161 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68006

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000400 Hom.: 0

Bravo AF: 0.00125

ExAC AF: 0.00196 AC: 214

Asia WGS AF: 0.0170 AC: 58 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.19
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.014
Sift	Benign	0.23	T
Sift4G	Benign	0.44	T
Polyphen		0.0030	B
Vest4		0.054
MVP		0.15
MPC		0.28
ClinPred		0.0015	T
GERP RS		-0.45
Varity_R		0.10
gMVP		0.070
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: rs142933317; hg19: chr19-18266699; COSMIC: COSV53227621;