chr12-18282518-C-T

Position:

• chr12-18282518-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001288772.2(PIK3C2G):​c.437C>T​(p.Pro146Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,605,944 control chromosomes in the GnomAD database, including 129,634 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.39 (11346 hom., cov: 32)
  • Exomes 𝑓: 0.40 (118288 hom.)
• Consequence: PIK3C2G NM_001288772.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.673

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001938343).
• BP6: Variant 12-18282518-C-T is Benign according to our data. Variant chr12-18282518-C-T is described in ClinVar as [Benign]. Clinvar id is 1297186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3C2G	NM_001288772.2	c.437C>T	p.Pro146Leu	missense_variant	2/33	ENST00000538779.6	NP_001275701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3C2G	ENST00000538779.6	c.437C>T	p.Pro146Leu	missense_variant	2/33	5	NM_001288772.2	ENSP00000445381	P1

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58798 AN: 151824 Hom.: 11343 Cov.: 32

Gnomad AFR AF: 0.358

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.389

GnomAD3 exomes AF: 0.386 AC: 95478 AN: 247226 Hom.: 18811 AF XY: 0.384 AC XY: 51580 AN XY: 134264

Gnomad AFR exome AF: 0.357

Gnomad AMR exome AF: 0.394

Gnomad ASJ exome AF: 0.369

Gnomad EAS exome AF: 0.268

Gnomad SAS exome AF: 0.339

Gnomad FIN exome AF: 0.440

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.387

GnomAD4 exome AF: 0.401 AC: 582385 AN: 1454002 Hom.: 118288 Cov.: 32 AF XY: 0.398 AC XY: 288401 AN XY: 723720

Gnomad4 AFR exome AF: 0.358

Gnomad4 AMR exome AF: 0.393

Gnomad4 ASJ exome AF: 0.371

Gnomad4 EAS exome AF: 0.258

Gnomad4 SAS exome AF: 0.342

Gnomad4 FIN exome AF: 0.435

Gnomad4 NFE exome AF: 0.412

Gnomad4 OTH exome AF: 0.386

GnomAD4 genome AF: 0.387 AC: 58817 AN: 151942 Hom.: 11346 Cov.: 32 AF XY: 0.385 AC XY: 28609 AN XY: 74238

Gnomad4 AFR AF: 0.357

Gnomad4 AMR AF: 0.387

Gnomad4 ASJ AF: 0.367

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.437

Gnomad4 NFE AF: 0.410

Gnomad4 OTH AF: 0.385

Alfa AF: 0.401 Hom.: 29201

Bravo AF: 0.384

TwinsUK AF: 0.409 AC: 1517

ALSPAC AF: 0.412 AC: 1588

ESP6500AA AF: 0.356 AC: 1290

ESP6500EA AF: 0.399 AC: 3252

ExAC AF: 0.385 AC: 46470

Asia WGS AF: 0.291 AC: 1014 AN: 3478

EpiCase AF: 0.403

EpiControl AF: 0.410

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2019	This variant is associated with the following publications: (PMID: 17991425) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.76
DEOGEN2	Benign	0.025	T;.;T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.67	T;T;T;.
MetaRNN	Benign	0.0019	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;.;L;L
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.8	D;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.047	D;T;T;T
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.0030, 0.0020	.;B;B;B
Vest4		0.047
MPC		0.012
ClinPred		0.0076	T
GERP RS		3.9
Varity_R		0.063
gMVP		0.29

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: rs11044004; hg19: chr12-18435452; COSMIC: COSV56799947; COSMIC: COSV56799947;