12-18286931-T-C

Position:

• chr12-18286931-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001288772.2(PIK3C2G):​c.761+2T>C variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIK3C2G NM_001288772.2 splice_donor
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.03

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]

LOC124902890 (HGNC:):

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-18286931-T-C is Pathogenic according to our data. Variant chr12-18286931-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 916567.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3C2G	NM_001288772.2	c.761+2T>C		splice_donor_variant		ENST00000538779.6	NP_001275701.1
LOC124902890	XR_007063233.1	n.160-1530A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3C2G	ENST00000538779.6	c.761+2T>C		splice_donor_variant		5	NM_001288772.2	ENSP00000445381	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1356692 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 673444

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Tracheoesophageal fistula Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Shen Lab, Columbia University Medical Center

Jul 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Benign	0.97
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	D;D;D;D
GERP RS		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.76		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1949470660; hg19: chr12-18439865; COSMIC: COSV56840958;