12-18282565-A-G

Variant names:

• chr12-18282565-A-G
• rs762601548
• NM_001288772.2:c.484A>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.484A>G​(p.Asn162Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N162H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PIK3C2G NM_001288772.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• 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=0.090855).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001288772.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3C2G	NM_001288772.2	MANE Select	c.484A>G	p.Asn162Asp	missense	Exon 2 of 33	NP_001275701.1	O75747-1
	PIK3C2G	NM_004570.6		c.484A>G	p.Asn162Asp	missense	Exon 2 of 32	NP_004561.3	O75747-2
	PIK3C2G	NM_001288774.2		c.-176A>G		5_prime_UTR	Exon 2 of 33	NP_001275703.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3C2G	ENST00000538779.6	TSL:5 MANE Select	c.484A>G	p.Asn162Asp	missense	Exon 2 of 33	ENSP00000445381.1	O75747-1
	PIK3C2G	ENST00000546003.5	TSL:1	n.484A>G		non_coding_transcript_exon	Exon 1 of 32	ENSP00000441618.1	F5GWG6
	PIK3C2G	ENST00000675017.1		c.484A>G	p.Asn162Asp	missense	Exon 2 of 33	ENSP00000501889.1	O75747-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247708 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459804 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726312

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110620

Other (OTH) AF: 0.00 AC: 0 AN: 60328

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.078
Sift	Benign	0.085	T
Sift4G	Benign	0.086	T
Polyphen		0.28	B
Vest4		0.16
MutPred		0.20		Gain of catalytic residue at N166 (P = 0.0082)
MVP		0.63
MPC		0.012
ClinPred		0.13	T
GERP RS		3.4
PromoterAI		-0.0045	Neutral
Varity_R		0.059
gMVP		0.15
Mutation Taster		=95/5	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

dbSNP: rs762601548; hg19: chr12-18435499;