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""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.49 | 6 bp |
| Donor Loss (DL) | 0.02 | 144 bp |
| Acceptor Gain (AG) | 0.95 | 1 bp |
| Donor Gain (DG) | 0.0 | -38 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the PVS1 rule is: "Null Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease". The evidence for this variant shows: it is an intronic change at c.353-6, outside the canonical ±1 or ±2 splice sites. Therefore, this criterion is not applied because the variant does not generate a null effect according to the PVS1 definition.
PS1 (Not Applied)
According to standard ACMG guidelines, the 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 is produced or documented. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the PS2 rule is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no parental or de novo data are available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the PS3 rule is: "Strong Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required". The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the PS4 rule is: "Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength is determined by aggregate points". The evidence for this variant shows: no case or phenotype data are reported. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the PM1 rule is: "Supporting Residues affecting critical functional domains provided in Table 4 for each gene". The evidence for this variant shows: it is intronic and not located in a defined critical domain. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the PM2 rule is: "Supporting Absent/rare from controls in an ethnically-matched cohort population sample ( ≥1)". The evidence for this variant shows: it is absent from population databases including gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the PM3 rule is: "For recessive disorders, detected in trans with a pathogenic variant". The evidence for this variant shows: no information on trans configuration with a pathogenic allele. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the PM4 rule is: "Protein length changes as a result of in-frame deletions/insertions in a non-repeat region". The evidence for this variant shows: no change to protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the PM5 rule is: "Novel missense change at an amino acid residue where a different missense change is pathogenic". The evidence for this variant shows: no amino acid change and no comparison to known pathogenic missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the PM6 rule is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the PP1 rule is: "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease". The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to VCEP guidelines, the PP2 rule is: "Supporting Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z-score > 3.09 (applicable to PIK3CA)". The evidence for this variant shows: it is not a missense variant. Therefore, this criterion is not applied.
PP3 (Supporting)
According to standard ACMG guidelines, the PP3 rule is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)". The evidence for this variant shows: SpliceAI predicts a high-impact splicing change (0.95 acceptor gain). Therefore, this criterion is applied at Supporting strength because computational tools predict a deleterious splicing effect.
PP4 (Not Applied)
According to standard ACMG guidelines, the PP4 rule is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no phenotype information is provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the PP5 rule is: "Reputable source recently reports variant as pathogenic, but evidence is not available to the laboratory to perform an independent evaluation". The evidence for this variant shows: no such reports exist. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the BA1 rule is: "Stand Alone Allele frequency (>0.0926%)". The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the BS1 rule is: "Strong Allele frequency (>0.0185%)". The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the BS2 rule is: "Strong Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygous in well phenotyped family members". The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the BS3 rule is: "Strong Follow recommendations set forth by the SVI in conjunction with the Brain Malformation Group for quality metrics and minimum validation controls". The evidence for this variant shows: no functional studies demonstrating no effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the BS4 rule is: "Lack of segregation in affected members of a family". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the BP1 rule is: "Missense variant in a gene for which primarily truncating variants are known to cause disease". The evidence for this variant shows: it is intronic. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the BP2 rule is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene". The evidence for this variant shows: no phase data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the BP3 rule is: "In-frame deletions/insertions in a repetitive region without a known function". The evidence for this variant shows: not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the BP4 rule is: "Supporting Award BP4 for synonymous, intronic positions (except canonical splice sites) or non-coding variants if two out of three splicing tools predict no impact". The evidence for this variant shows: high-impact splicing predicted by SpliceAI. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the BP5 rule is: "Variant found in a case with an alternative molecular basis for disease". The evidence for this variant shows: no alternative molecular diagnosis. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the BP6 rule is: "Reputable source reports as benign but evidence is not available". The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the BP7 rule is: "Supporting For synonymous, intronic positions (except canonical splice sites) and non-coding UTR variants, if the nucleotide is non-conserved (PhyloP <0.1)". The evidence for this variant shows: predicted to alter splicing. Therefore, this criterion is not applied.