12-18313998-A-C

Variant summary

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

The NM_001288772.2(PIK3C2G):c.1071A>C(p.Lys357Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,440,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PIK3C2G NM_001288772.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.08

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3C2G	NM_001288772.2	c.1071A>C	p.Lys357Asn	missense_variant	6/33	ENST00000538779.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3C2G	ENST00000538779.6	c.1071A>C	p.Lys357Asn	missense_variant	6/33	5	NM_001288772.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1440100 Hom.: 0 Cov.: 28 AF XY: 0.00000280 AC XY: 2 AN XY: 714156

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: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 01, 2022

The c.1071A>C (p.K357N) alteration is located in exon 6 (coding exon 5) of the PIK3C2G gene. This alteration results from a A to C substitution at nucleotide position 1071, causing the lysine (K) at amino acid position 357 to be replaced by an asparagine (N). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;T;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.81	T;T;T;.
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Benign	-0.41	T
MutationTaster	Benign	0.73	N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.37	N;N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.81
MutPred		0.52		Gain of catalytic residue at M354 (P = 0.0026);Gain of catalytic residue at M354 (P = 0.0026);Gain of catalytic residue at M354 (P = 0.0026);Gain of catalytic residue at M354 (P = 0.0026);
MVP		0.76
MPC		0.027
ClinPred		0.57	D
GERP RS		3.3
Varity_R		0.13
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-18466932;