11-17091552-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BS1_Supporting
The NM_002645.4(PIK3C2A):c.4747G>T(p.Asp1583Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,456,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
PIK3C2A
NM_002645.4 missense
NM_002645.4 missense
Scores
5
10
4
Clinical Significance
Conservation
PhyloP100: 6.12
Genes affected
PIK3C2A (HGNC:8971): (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha) 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. The PI3-kinase activity of this protein is not sensitive to nanomolar levels of the inhibitor wortmanin. This protein was shown to be able to be activated by insulin and may be involved in integrin-dependent signaling. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.82
BS1
?
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000343 (5/1456820) while in subpopulation AMR AF= 0.000112 (5/44494). AF 95% confidence interval is 0.0000438. There are 0 homozygotes in gnomad4_exome. There are 2 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIK3C2A | NM_002645.4 | c.4747G>T | p.Asp1583Tyr | missense_variant | 31/33 | ENST00000691414.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIK3C2A | ENST00000691414.1 | c.4747G>T | p.Asp1583Tyr | missense_variant | 31/33 | NM_002645.4 | P1 | ||
PIK3C2A | ENST00000265970.11 | c.4747G>T | p.Asp1583Tyr | missense_variant | 30/32 | 1 | P1 | ||
PIK3C2A | ENST00000531428.1 | n.1269G>T | non_coding_transcript_exon_variant | 11/13 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250068Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135100
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GnomAD4 exome AF: 0.00000343 AC: 5AN: 1456820Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2AN XY: 724986
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GnomAD4 genome ? Cov.: 32
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 14, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with PIK3C2A-related conditions. This variant is present in population databases (rs763977292, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 1583 of the PIK3C2A protein (p.Asp1583Tyr). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
T
Polyphen
D
Vest4
MutPred
Gain of ubiquitination at K1582 (P = 0.0597);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at