Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000314.8 | MANE Select | 8515 nt | 846–2057 |
| NM_000314.7 | RefSeq Select | 8514 nt | 845–2056 |
| NM_000314.5 | Alternative | 8719 nt | 1032–2243 |
| NM_000314.4 | Alternative | 5572 nt | 1032–2243 |
| NM_000314.3 | Alternative | 3416 nt | 1032–2243 |
| NM_000314.6 | Alternative | 8718 nt | 1032–2243 |
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) | 1.0 | 2 bp |
| Donor Loss (DL) | 0.59 | 45 bp |
| Acceptor Gain (AG) | 0.4 | 14 bp |
| Donor Gain (DG) | 0.0 | 405 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: 'Very Strong Strength: Very Strong Use PTEN PVS1 decision tree.' The evidence for this variant shows: c.210-1delG disrupts the canonical splice acceptor site predicted to abolish normal splicing (loss-of-function). Therefore, this criterion is applied at Very Strong strength because canonical splice site variants in PTEN are interpreted as null variants under the PVS1 decision tree.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: 'Strong Strength: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant.' The evidence for this variant shows: no previously established pathogenic variant at this nucleotide or amino acid position. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: 'Strong Strength: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.' The evidence for this variant shows: no data on de novo occurrence with confirmed parental relationships. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: 'Strong Strength: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (RNA, mini-gene, or other assay shows impact on splicing).' 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 rule for PS4 is: 'Strong Strength: Probands with specificity score 4–15.5 OR increased prevalence in affected versus controls.' The evidence for this variant shows: no case or cohort data available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: 'Moderate Strength: Located in a mutational hot spot and/or critical and well-established functional domain (residues 90–94, 123–130, 166–168).' The evidence for this variant shows: c.210-1 is outside the defined PTEN hotspots/domains. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: 'Supporting Strength: Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%).' The evidence for this variant shows: not observed in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from control populations.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant on the other allele.' The evidence for this variant shows: PTEN-related disease is autosomal dominant and no trans allelic data are available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: 'Moderate Strength: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.' The evidence for this variant shows: c.210-1delG is a splice site variant, not an in-frame indel. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: 'Moderate Strength: Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.' The evidence for this variant shows: it is not a missense variant. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: 'Strong Strength: Two probands with presumed de novo occurrence or similar.' The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: 'Supporting Strength: Co-segregation with disease in multiple affected family members, with 3–4 meioses observed.' The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Supporting Strength: Missense variant in a gene with a low rate of benign missense variation where missense is a common mechanism.' The evidence for this variant shows: it is a splice variant, not missense. Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: 'Supporting Strength: Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak.' The evidence for this variant shows: SpliceAI predicts a maximum acceptor loss score of 1.0. Therefore, this criterion is applied at Supporting strength because computational tools concordantly predict a splice defect.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting Strength: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no phenotypic data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting Strength: Reputable source has classified the variant as pathogenic.' The evidence for this variant shows: not found in ClinVar or other reputable databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone Strength: gnomAD Filtering allele frequency >0.00056 (0.056%).' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Strong Strength: gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%).' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: 'Strong Strength: Observed in the homozygous state in a healthy or PHTS-unaffected individual.' The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Strong Strength: Functional studies show no damaging effect.' The evidence for this variant shows: no functional studies performed. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: 'Strong Strength: Lack of segregation in affected members of two or more families.' The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Supporting Strength: Missense variant in a gene where only LOF causes disease.' The evidence for this variant shows: it is a splice-site variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Supporting Strength: Observed in trans with a pathogenic variant in a recessive gene.' The evidence for this variant shows: PTEN is dominant and no cis/trans data available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'Supporting Strength: In-frame indels in a repetitive region without known function.' The evidence for this variant shows: it is a splice-site deletion, not an in-frame indel in a repeat region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'Supporting Strength: Multiple lines of computational evidence suggest no impact on gene or gene product.' The evidence for this variant shows: computational tools predict a damaging splice effect. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Supporting Strength: Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Supporting Strength: Variant classification by a reputable source but without accessible evidence.' The evidence for this variant shows: no such classification exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Supporting Strength: A synonymous or intronic variant at or beyond +7/-21 with no predicted splicing impact.' The evidence for this variant shows: it lies at -1 within the splice consensus and is predicted to impact splicing. Therefore, this criterion is not applied.