19-18169144-C-A

Variant names:

• chr19-18169144-C-A
• rs112163556
• NM_005027.4:c.2037C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005027.4(PIK3R2):​c.2037C>A​(p.Phe679Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F679F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.693
• 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: Labcorp Genetics (formerly Invitae), Illumina, G2P, 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R2	NM_005027.4	c.2037C>A	p.Phe679Leu	missense_variant	Exon 16 of 16	ENST00000222254.13	NP_005018.2
PIK3R2	NR_073517.2	n.2641C>A		non_coding_transcript_exon_variant	Exon 16 of 16
PIK3R2	NR_162071.1	n.2379C>A		non_coding_transcript_exon_variant	Exon 15 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R2	ENST00000222254.13	c.2037C>A	p.Phe679Leu	missense_variant	Exon 16 of 16	1	NM_005027.4	ENSP00000222254.6
ENSG00000268173	ENST00000593731.1	n.2037C>A		non_coding_transcript_exon_variant	Exon 16 of 25	2		ENSP00000471914.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.33	N
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		-0.69
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.3	D;.
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.63		Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);
MVP		0.84
MPC		2.1
ClinPred		1.0	D
GERP RS		-0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.63
Mutation Taster		=13/87	disease causing

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: rs112163556; hg19: chr19-18279954;