Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_006218.2 | Alternative | 3724 nt | 158–3364 |
| NM_006218.3 | Alternative | 9104 nt | 158–3364 |
| NM_006218.4 | MANE Select | 9259 nt | 324–3530 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Benign (3 clinical laboratories) and as Uncertain significance (1 clinical laboratories) and as Likely benign (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.12 | -48 bp |
| Donor Loss (DL) | 0.0 | -190 bp |
| Acceptor Gain (AG) | 0.0 | 50 bp |
| Donor Gain (DG) | 0.0 | -100 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, PVS1 rule is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows it is synonymous (A995=) and not predicted to affect splice sites at canonical positions. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to standard ACMG guidelines, PS1 rule is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows no amino acid change (synonymous), so PS1 is not applied.
PS2 (Not Applied)
According to VCEP guidelines, PS2 requires confirmed de novo occurrence with maternity and paternity and/or tissue mosaicism evidence. No de novo or mosaicism data are available for this variant. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, PS3 rule is: "Well‐established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." No functional studies are available for this variant. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines, PS4 requires phenotypic case‐control evidence with point scoring and absence from controls (PM2). No case reports or statistical evidence exist for this variant. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 Supporting is: "Residues affecting critical functional domains provided in Table 4 for each gene." This variant is synonymous and does not affect a critical domain. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines, PM2 Supporting is: "Absent/rare from controls in an ethnically-matched cohort population sample (≥1)." The evidence for this variant shows a maximum gnomAD MAF of 0.0607% (170/280,120 alleles, 2 homozygotes), which is below common thresholds and qualifies as rare. Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, PM3 rule is: "For recessive disorders, detected in trans with a pathogenic variant." No information on trans configuration with another variant is available. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 rule is: "Protein length changes due to in-frame deletions/insertions." This variant is synonymous and does not change protein length. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines, PM5 Moderate is: "Novel missense change at an amino acid where a different missense change is pathogenic." This variant is synonymous. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 rule is: "Assumed de novo, without confirmation of paternity and maternity." No de novo data are available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, PP1 rule is: "Co-segregation with disease in multiple affected family members." No segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to VCEP guidelines for PIK3CA, PP2 Supporting is: "Missense constraint z-score >3.09." This variant is synonymous, not missense. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, PP3 rule is: "Multiple lines of computational evidence support a deleterious effect." In silico predictors show predominantly benign results (CADD 0.53, SpliceAI 0.12), so no evidence for deleterious effect. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 rule is: "Patient’s phenotype or family history highly specific for a disease with a single genetic cause." No phenotype data are provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 rule is: "Reputable source reports variant as pathogenic without evidence." ClinVar reports are conflicting (Benign, Likely Benign, VUS). No single reputable source supports pathogenic. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 Stand Alone is: "Allele frequency >0.0926%." The variant MAF is 0.0607%, below the threshold. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 Strong is: "Allele frequency >0.0185%." The variant MAF of 0.0607% (0.000607) is below 0.0185 (1.85%). Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 Strong is: "≥3 homozygotes in gnomAD or ≥3 heterozygous well-phenotyped family members." Only 2 homozygotes are observed. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 Strong requires well-established functional studies showing no damaging effect. No such studies exist. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, BS4 rule is: "Lack of segregation in affected members of a family." No segregation data are available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 rule is: "Missense variant in a gene where only loss-of-function causes disease." This variant is synonymous. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 rule is: "Observed in trans with a pathogenic variant (for dominant) or in cis with pathogenic variant." No such data exist. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 rule is: "In-frame deletions/insertions in a repetitive region without known function." This variant is synonymous. Therefore, BP3 is not applied.
BP4 (Supporting)
According to VCEP guidelines, BP4 Supporting is: "For synonymous variants, if two of three splicing tools predict no impact on splicing." SpliceAI predicts minimal impact (0.12), and in silico splicing predictors are concordant for no effect. Therefore, BP4 is applied at Supporting strength.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 rule is: "Variant found in a case with an alternate molecular basis for disease." No such evidence exists. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 rule is: "Reputable source reports variant as benign without evidence." ClinVar submissions are conflicting; no single source meets criteria. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, BP7 Supporting is: "Synonymous variant at non-conserved nucleotide (PhyloP <0.1)." No conservation data (PhyloP) are provided. Therefore, BP7 is not applied.