19-18167251-A-G

Position:

• chr19-18167251-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_005027.4(PIK3R2):​c.1681A>G​(p.Asn561Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.14

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]

ENSG00000268173 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791
• PP5: Variant 19-18167251-A-G is Pathogenic according to our data. Variant chr19-18167251-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376165.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3R2	NM_005027.4	c.1681A>G	p.Asn561Asp	missense_variant	13/16	ENST00000222254.13	NP_005018.2
PIK3R2	NR_073517.2	n.2285A>G		non_coding_transcript_exon_variant	13/16
PIK3R2	NR_162071.1	n.2019A>G		non_coding_transcript_exon_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3R2	ENST00000222254.13	c.1681A>G	p.Asn561Asp	missense_variant	13/16	1	NM_005027.4	ENSP00000222254.6
ENSG00000268173	ENST00000593731.1	n.1681A>G		non_coding_transcript_exon_variant	13/25	2		ENSP00000471914.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.31; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PIK3R2 related disorder (ClinVar ID: VCV000376165). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.024	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.28		Loss of MoRF binding (P = 0.0393);Loss of MoRF binding (P = 0.0393);
MVP		0.50
MPC		1.5
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.76
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519801; hg19: chr19-18278061; COSMIC: COSV55847533; COSMIC: COSV55847533;