About PIK3R1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3R1 c.2079A>T, p.(Glu693Asp)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen PIK3R1 VCEP v1.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_181523.2:c.2079A>T is absent from gnomAD v4.1 (total allele frequency = 0), meeting the VCEP PM2_Supporting threshold of total allele frequency <0.00000132.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen Antibody Deficiencies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PIK3R1 Version 1.0.0 v1.0.0 point-based framework: PM2 supporting (+1) = 1 points, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PIK3R1, the regulatory subunit of PI3-kinase, is mutated in various cancers, most frequently in glioma, endometrial and colorectal cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PIK3R1 VCEP v1.0.0, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 15 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_181523.2:c.2079A>T (p.Glu693Asp) is a missense variant in PIK3R1 that is absent from gnomAD v4.1, meeting PM2_Supporting under the ClinGen Antibody Deficiencies VCEP specifications (AF < 0.00000132).
The variant does not meet PP3 (REVEL 0.467 < 0.644 threshold) or BP4 (REVEL 0.467 > 0.290 threshold). SpliceAI predicts no splice impact (max delta = 0.00).
No variant-specific functional data, de novo reports, co-segregation data, or proband phenotype data are available. The variant is absent from ClinVar and has not been reported in the literature.
PVS1, PS1, PS2, PS3, PS4, PP1, PP3, PP4, BA1, BS1, BS3, BS4, BP4, BP5, and BP7 are not met. PM1, PM5, PM6 (use PS2 instead), PP2, PP5, BS2, BP1, BP2, and BP6 are not applicable under VCEP specifications.
Total Bayesian points: +1 (PM2_Supporting). Under the Tavtigian et al. 2020 point scale adopted by the Antibody Deficiencies VCEP, 0–5 points corresponds to a classification of Uncertain Significance.
No criteria match.
Met · 1
PM2 SupportingNM_181523.2:c.2079A>T is absent from gnomAD v4.1 (total allele frequency = 0), meeting the VCEP PM2_Supporting threshold of total allele frequency <0.00000132. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v4.1 (AF = 0.0).
- VCEP PM2_Supporting threshold: AF < 0.00000132.
Sources
Not met · 15 · evaluated, threshold not reached
PVS1 NM_181523.2:c.2079A>T is a missense variant encoding p.Glu693Asp. The VCEP PVS1 rules apply only to nonsense, frameshift, or canonical splice variants that introduce premature stop codons in specified regions, or to missense/synonymous/intronic variants with SpliceAI delta >0.2 AND experimental evidence of abnormal splicing. This variant has SpliceAI max delta score of 0.00 and no experimental evidence of splicing impact; therefore it does not meet any PVS1 strength threshold. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00 — no predicted splice impact.
- Variant is a missense substitution (p.Glu693Asp)
- not a null variant eligible for PVS1 under VCEP rules.
Sources
PS1 No other missense variant encoding the same amino acid change (p.Glu693Asp) has been classified as pathogenic or likely pathogenic by the Antibody Deficiencies VCEP. The variant is absent from ClinVar and no prior VCEP classification exists for this residue. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no VCEP-classified comparator exists at codon 693.
Sources
PS2 No de novo occurrence of NM_181523.2:c.2079A>T has been reported in a patient with PIK3R1-related immunodeficiency. No publications or clinical records document this variant as de novo with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar
- literature
- or clinical databases.
Still missing
- De novo status cannot be assessed without proband data.
PS3 No variant-specific functional data are available for NM_181523.2:c.2079A>T (p.Glu693Asp). The VCEP-approved functional assays (lipid kinase activity, AKT kinase activity, protein binding, conformational dynamics, pS6/pAKT enrichment ratio) have not been tested for this variant. Details ▾Hide ▴
Evidence considered
- VCEP functional assay spreadsheet does not include p.Glu693Asp among tested variants.
- The published assays tested c.1425+1G>T
- c.1425+1G>C
- and p85α Δexon11 variants only.
Still missing
- No functional data available for this specific missense variant.
Sources
vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
PS4 No probands harboring NM_181523.2:c.2079A>T have been reported in the literature or clinical databases. The VCEP PS4 requires at least 1 proband meeting phenotype scoring criteria (≥6 points on Table 3 with PIK3CD locus excluded, or ≥10 points without gene panel). Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no affected individuals reported.
- No proband data available for phenotype scoring under VCEP PS4 rubric.
Still missing
- No proband data available.
Sources
PP1 No co-segregation data are available for NM_181523.2:c.2079A>T with PIK3R1-related immunodeficiency. The VCEP requires at least 1 affected meiosis (proband + 1 affected first-degree relative) for PP1_Supporting. Details ▾Hide ▴
Evidence considered
- No family studies or co-segregation data reported for this variant.
Still missing
- No family or co-segregation data available.
PP3 REVEL score of 0.467 is below the VCEP PP3 threshold of ≥0.644, and SpliceAI max delta score is 0.00 (below the ≥0.2 threshold). The VCEP PP3 criteria are not satisfied. Details ▾Hide ▴
Evidence considered
- REVEL = 0.467 (threshold ≥0.644 not met).
- SpliceAI max delta = 0.00 (threshold ≥0.2 not met).
- BayesDel = 0.0115.
Sources
revelspliceai ↗
PP4 No proband phenotype data are available for NM_181523.2:c.2079A>T. The VCEP PP4 requires a proband scoring ≥10 phenotype points on the PS4 counting rubric with genotyping excluding PIK3CD locus variants. Details ▾Hide ▴
Evidence considered
- No proband reported with this variant.
Still missing
- No proband phenotype data available.
BA1 NM_181523.2:c.2079A>T is absent from gnomAD v4.1 and does not meet the VCEP BA1 threshold of GrpMax filtering allele frequency ≥0.00316. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v4.1
- allele frequency = 0.
- VCEP BA1 threshold: GrpMax FAF ≥ 0.00316.
Sources
BS1 NM_181523.2:c.2079A>T is absent from gnomAD v4.1 and does not meet the VCEP BS1 threshold of GrpMax filtering allele frequency ≥0.000316. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v4.1
- allele frequency = 0.
- VCEP BS1 threshold: GrpMax FAF ≥ 0.000316.
Sources
BS3 No variant-specific functional data demonstrating a non-damaging effect are available for NM_181523.2:c.2079A>T (p.Glu693Asp). The variant has not been tested in any VCEP-approved functional assay. Details ▾Hide ▴
Evidence considered
- VCEP functional assay spreadsheet does not include p.Glu693Asp.
- No OddsPath <0.053 data available for any approved assay.
Still missing
- No functional data available for this variant.
Sources
vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
BS4 No segregation data are available for NM_181523.2:c.2079A>T. The VCEP BS4 requires at least 1 affected family member (scoring ≥6 phenotype points) lacking the variant. Details ▾Hide ▴
Evidence considered
- No family studies or lack-of-segregation data reported.
Still missing
- No segregation data available.
BP4 REVEL score of 0.467 exceeds the VCEP BP4 threshold of ≤0.290. The VCEP BP4 criteria require both REVEL ≤0.290 and CADD ≤21.5 with SpliceAI delta scores <0.1. The REVEL threshold is not satisfied. Details ▾Hide ▴
Evidence considered
- REVEL = 0.467 (threshold ≤0.290 not met).
- SpliceAI max delta = 0.00 (threshold <0.1 met).
Sources
revelspliceai ↗
BP5 No proband data are available demonstrating an alternative molecular basis for disease. The VCEP BP5 requires at least 2 cases with an alternative molecular basis. Details ▾Hide ▴
Evidence considered
- No cases with alternative molecular diagnosis reported for probands harboring this variant.
Still missing
- No proband data available to assess alternative molecular basis.
BP7 The VCEP BP7_Supporting rule applies to synonymous and intronic variants, not missense variants. BP7_Strong (RNA) requires experimental evidence of no impact on splicing, which is not available for this variant. NM_181523.2:c.2079A>T is a missense variant and does not satisfy any BP7 strength rule. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous or intronic — BP7_Supporting not applicable.
- No RNA-based experimental evidence available — BP7_Strong (RNA) not met.
- SpliceAI max delta = 0.00.
Still missing
- No RNA splicing data available.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PM1 VCEPPM1 is explicitly designated as Not Applicable by the Antibody Deficiencies VCEP for PIK3R1. Details ▾Hide ▴
PM5 N/AThe Antibody Deficiencies VCEP instructs that PM5 is not to be applied to missense variants in PIK3R1, given that missense variation is not a well-described contributor to PIK3R1-related APDS. Details ▾Hide ▴
Evidence considered
- VCEP criteria.json instructionsToUse: 'Do not apply to missense variants given that missense variation is not a well-described contributor to PIK3R1-related APDS.'
- Variant is a missense substitution (p.Glu693Asp).
Sources
PM6 VCEPPM6 is explicitly designated as Not Applicable by the Antibody Deficiencies VCEP. Assumed de novo occurrences are assessed under PS2 instead. Details ▾Hide ▴
PP2 VCEPPP2 is explicitly designated as Not Applicable by the Antibody Deficiencies VCEP. The gnomAD v2.1.1 missense Z score for PIK3R1 (Z = 2.72) indicates the gene is not constrained for missense variation, and both benign and pathogenic missense variants exist. Details ▾Hide ▴
PP5 VCEPPP5 is explicitly designated as Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- VCEP criteria.json: PP5 applicability = Not Applicable for this VCEP.
Sources
BS2 VCEPBS2 is explicitly designated as Not Applicable by the Antibody Deficiencies VCEP due to incomplete penetrance and variable expressivity of PIK3R1-related disease. Details ▾Hide ▴
BP1 VCEPBP1 is explicitly designated as Not Applicable by the Antibody Deficiencies VCEP because pathogenic PIK3R1 variants are not limited to truncating variants but include missense variants as well. Details ▾Hide ▴
BP2 VCEPBP2 is explicitly designated as Not Applicable by the Antibody Deficiencies VCEP because the field does not understand all potential allelic mechanisms associated with PIK3R1 variants, and diverse combinatorial variant effects cannot be excluded. Details ▾Hide ▴
BP6 VCEPBP6 is explicitly designated as Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- VCEP criteria.json: BP6 applicability = Not Applicable for this VCEP.
Sources
PS5 N/APS5 is not included in the Antibody Deficiencies VCEP specifications for PIK3R1. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PIK3R1
- Transcript
- NM_181523.2
- Coding (HGVS c.)
- NM_181523.2:c.2079A>T
- Protein (HGVS p.)
- NP_852664.1:p.(Glu693Asp)
- GRCh38
- chr5:68297505 A>T
- GRCh37
- chr5:67593333 A>T
Gene diagram
Every interpreted variant in PIK3R1, mapped onto the exon structure of NM_181523.2. Select a row to find it on the plot.
PIK3R1NM_181523.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PIK3R1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.467
- BayesDel
- 0.012
How the predictions were used
PP3 REVEL score of 0.467 is below the VCEP PP3 threshold of ≥0.644, and SpliceAI max delta score is 0.00 (below the ≥0.2 threshold). The VCEP PP3 criteria are not satisfied. Details ▾Hide ▴
Evidence considered
- REVEL = 0.467 (threshold ≥0.644 not met).
- SpliceAI max delta = 0.00 (threshold ≥0.2 not met).
- BayesDel = 0.0115.
Sources
revelspliceai ↗
BP4 REVEL score of 0.467 exceeds the VCEP BP4 threshold of ≤0.290. The VCEP BP4 criteria require both REVEL ≤0.290 and CADD ≤21.5 with SpliceAI delta scores <0.1. The REVEL threshold is not satisfied. Details ▾Hide ▴
Evidence considered
- REVEL = 0.467 (threshold ≤0.290 not met).
- SpliceAI max delta = 0.00 (threshold <0.1 met).
Sources
revelspliceai ↗
BP7 The VCEP BP7_Supporting rule applies to synonymous and intronic variants, not missense variants. BP7_Strong (RNA) requires experimental evidence of no impact on splicing, which is not available for this variant. NM_181523.2:c.2079A>T is a missense variant and does not satisfy any BP7 strength rule. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous or intronic — BP7_Supporting not applicable.
- No RNA-based experimental evidence available — BP7_Strong (RNA) not met.
- SpliceAI max delta = 0.00.
Still missing
- No RNA splicing data available.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.467. BayesDel score = 0.0115145.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1626566541
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_181523.2%3Ac.2079A%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-67593333-A-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-68297505-A-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-68297505-A-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_181523.2%3Ac.2079…
- OncoKB ↗www.oncokb.org/gene/PIK3R1/E693D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PIK3R1+c.2079A%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.467. BayesDel score = 0.0115145.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PIK3R1, the regulatory subunit of PI3-kinase, is mutated in various cancers, most frequently in glioma, endometrial and colorectal cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.