12-18321001-C-A

Position:

• chr12-18321001-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001288772.2(PIK3C2G):​c.1177C>A​(p.Leu393Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,418,678 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: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PIK3C2G NM_001288772.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.777

Genes affected

PIK3C2G (HGNC:8973): (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 gamma) The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3-kinases. C2 domains act as calcium-dependent phospholipid binding motifs that mediate translocation of proteins to membranes, and may also mediate protein-protein interactions. This gene may play a role in several diseases, including type II diabetes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32029337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3C2G	NM_001288772.2	c.1177C>A	p.Leu393Ile	missense_variant	7/33	ENST00000538779.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3C2G	ENST00000538779.6	c.1177C>A	p.Leu393Ile	missense_variant	7/33	5	NM_001288772.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1418678 Hom.: 0 Cov.: 24 AF XY: 0.00000283 AC XY: 2 AN XY: 707506

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2021

The c.1177C>A (p.L393I) alteration is located in exon 7 (coding exon 6) of the PIK3C2G gene. This alteration results from a C to A substitution at nucleotide position 1177, causing the leucine (L) at amino acid position 393 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T;.;T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.77	T;T;T;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.34	N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.056	T;T;T;T
Sift4G	Pathogenic	0.0	D;T;T;T
Polyphen		0.99, 0.99	.;D;D;D
Vest4		0.28
MutPred		0.45		Gain of catalytic residue at E394 (P = 0.0119);Gain of catalytic residue at E394 (P = 0.0119);Gain of catalytic residue at E394 (P = 0.0119);Gain of catalytic residue at E394 (P = 0.0119);
MVP		0.57
MPC		0.015
ClinPred		0.89	D
GERP RS		4.6
Varity_R		0.15
gMVP		0.035

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1444567095; hg19: chr12-18473935;