12-18282409-A-G

Variant names:

• chr12-18282409-A-G
• NM_001288772.2:c.328A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001288772.2(PIK3C2G):​c.328A>G​(p.Ser110Gly) 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 benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3C2G NM_001288772.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13
• Publications: 0 publications found

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]

RERGL (HGNC:26213): (RERG like) Predicted to enable G protein activity and GTP binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16017258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3C2G	NM_001288772.2	c.328A>G	p.Ser110Gly	missense_variant	Exon 2 of 33	ENST00000538779.6	NP_001275701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3C2G	ENST00000538779.6	c.328A>G	p.Ser110Gly	missense_variant	Exon 2 of 33	5	NM_001288772.2	ENSP00000445381.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.328A>G (p.S110G) alteration is located in exon 2 (coding exon 1) of the PIK3C2G gene. This alteration results from a A to G substitution at nucleotide position 328, causing the serine (S) at amino acid position 110 to be replaced by a glycine (G). 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	0.083
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T;.;T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.73	T;T;T;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	.;.;L;L
PhyloP100		3.1
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.90	N;N;N;N
REVEL	Benign	0.090
Sift	Benign	0.066	T;T;T;T
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.082, 0.049	.;B;B;B
Vest4		0.089
MutPred		0.30		Gain of catalytic residue at S110 (P = 9e-04);Gain of catalytic residue at S110 (P = 9e-04);Gain of catalytic residue at S110 (P = 9e-04);Gain of catalytic residue at S110 (P = 9e-04);
MVP		0.66
MPC		0.012
ClinPred		0.58	D
GERP RS		4.8
PromoterAI		-0.0078	Neutral
Varity_R		0.095
gMVP		0.14
Mutation Taster		=91/9	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

hg19: chr12-18435343;