12-18338432-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001288772.2(PIK3C2G):c.1279G>A(p.Val427Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,560,410 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: PIK3C2G NM_001288772.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0210

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08900535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3C2G	NM_001288772.2	c.1279G>A	p.Val427Met	missense_variant	9/33	ENST00000538779.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3C2G	ENST00000538779.6	c.1279G>A	p.Val427Met	missense_variant	9/33	5	NM_001288772.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000375 AC: 9 AN: 240084 Hom.: 0 AF XY: 0.0000308 AC XY: 4 AN XY: 130076

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.000124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000567

Gnomad SAS exome AF: 0.0000354

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000910

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 25 AN: 1408392 Hom.: 0 Cov.: 26 AF XY: 0.0000199 AC XY: 14 AN XY: 702822

Gnomad4 AFR exome AF: 0.000125

Gnomad4 AMR exome AF: 0.000141

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000842

Gnomad4 OTH exome AF: 0.0000342

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152018 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74228

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000331 AC: 4

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

Aug 12, 2021

The c.1279G>A (p.V427M) alteration is located in exon 9 (coding exon 8) of the PIK3C2G gene. This alteration results from a G to A substitution at nucleotide position 1279, causing the valine (V) at amino acid position 427 to be replaced by a methionine (M). 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	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	7.2
Dann	Benign	0.94
DEOGEN2	Benign	0.030	T;.;T;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.65	T;T;T;.
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.089	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.76	N;N;N;N
REVEL	Benign	0.028
Sift	Benign	0.089	T;T;T;T
Sift4G	Benign	0.094	T;T;T;T
Polyphen		0.038, 0.46	.;B;P;P
Vest4		0.19
MutPred		0.30		Gain of catalytic residue at Q424 (P = 0.0238);Gain of catalytic residue at Q424 (P = 0.0238);Gain of catalytic residue at Q424 (P = 0.0238);Gain of catalytic residue at Q424 (P = 0.0238);
MVP		0.30
MPC		0.018
ClinPred		0.025	T
GERP RS		-0.99
Varity_R		0.036
gMVP		0.094

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs756781973; hg19: chr12-18491366;