Genetic Variant NM_001288772.2:c.761+2T>A (chr12-18286931-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001288772.2(PIK3C2G):c.761+2T>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000737 in 1,356,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

PIK3C2G
NM_001288772.2 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.03

Publications

0 publications found

Variant links:

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]

PIK3C2G links:

RERGL (HGNC:26213): (RERG like) Predicted to enable G protein activity and GTP binding activity. [provided by Alliance of Genome Resources, Apr 2022]

RERGL links:

LOC124902890 (HGNC:):

LOC124902890 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PIK3C2G	NM_001288772.2	MANE Select	c.761+2T>A	splice_donor intron	N/A	NP_001275701.1	O75747-1
PIK3C2G	NM_004570.6		c.761+2T>A	splice_donor intron	N/A	NP_004561.3	O75747-2
PIK3C2G	NM_001288774.2		c.95+2T>A	splice_donor intron	N/A	NP_001275703.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.37e-7

AC:

AN:

1356692

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

673444

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30374

American (AMR)

AF:

0.00

AC:

AN:

34734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24424

East Asian (EAS)

AF:

0.00

AC:

AN:

36508

South Asian (SAS)

AF:

0.0000134

AC:

AN:

74864

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5560

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1043352

Other (OTH)

AF:

0.00

AC:

AN:

56534

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

0.97

Eigen

Pathogenic

0.81

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.89

PhyloP100

4.0

GERP RS

4.0

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.76

SpliceAI score (max)

0.77

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.77

Position offset: -2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over