NM_001288772.2:c.761+2T>C

Variant names:

• chr12-18286931-T-C
• rs1949470660
• NM_001288772.2:c.761+2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001288772.2(PIK3C2G):​c.761+2T>C variant causes a splice donor, intron 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, intron
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.03
• 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]

LOC124902890 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 916567.Status of the report is no_assertion_criteria_provided, 0 stars.

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.761+2T>C		splice_donor intron	N/A	NP_001275701.1	O75747-1
	PIK3C2G	NM_004570.6		c.761+2T>C		splice_donor intron	N/A	NP_004561.3	O75747-2
	PIK3C2G	NM_001288774.2		c.95+2T>C		splice_donor intron	N/A	NP_001275703.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3C2G	ENST00000538779.6	TSL:5 MANE Select	c.761+2T>C		splice_donor intron	N/A	ENSP00000445381.1	O75747-1
	PIK3C2G	ENST00000546003.5	TSL:1	n.*58+2T>C		splice_donor intron	N/A	ENSP00000441618.1	F5GWG6
	PIK3C2G	ENST00000675017.1		c.761+2T>C		splice_donor intron	N/A	ENSP00000501889.1	O75747-1

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

African (AFR) AF: 0.00 AC: 0 AN: 30374

American (AMR) AF: 0.00 AC: 0 AN: 34734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24424

East Asian (EAS) AF: 0.00 AC: 0 AN: 36508

South Asian (SAS) AF: 0.00 AC: 0 AN: 74864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1043352

Other (OTH) AF: 0.00 AC: 0 AN: 56534

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Esophageal atresia/tracheoesophageal fistula (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.0
GERP RS		4.0
Mutation Taster		=12/88	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1949470660; hg19: chr12-18439865;