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).1 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).2 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.3 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.4 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.5
PIK3R1
Final classification
VUS
PM2
PIK3R1
c.2079A>T
p.Glu693Asp
This variant
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).
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.
Classification rationale
PM2
VUS
PIK3R1 c.2079A>T
PM2
→
VUS
2
revelspliceai ↗
3
clinvar ↗vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
4
cspec ↗pvs1_variant_assessment
5
final_classification_frameworkvcep_bayesian_rules_variant_classification_pik3r1
Gene diagram
· NM_181523.2 · variants mapped to exon structure
PIK3R1
NM_181523.2
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Variant absent from gnomAD v4.1 (AF = 0.0).VCEP PM2_Supporting threshold: AF < 0.00000132.
Assessed · not applied
· 15 not met · 0 not assessed
Pathogenic
PVS1
NM_181523.2:c.2079A>T is a missense variant encoding p.Glu693Asp.
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.
PS2
No de novo occurrence of NM_181523.2:c.2079A>T has been reported in a patient with PIK3R1-related immunodeficiency.
PS3
No variant-specific functional data are available for NM_181523.2:c.2079A>T (p.Glu693Asp).
PS4
No probands harboring NM_181523.2:c.2079A>T have been reported in the literature or clinical databases.
PP1
No co-segregation data are available for NM_181523.2:c.2079A>T with PIK3R1-related immunodeficiency.
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).
PP4
No proband phenotype data are available for NM_181523.2:c.2079A>T.
Benign
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.
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.
BS3
No variant-specific functional data demonstrating a non-damaging effect are available for NM_181523.2:c.2079A>T (p.Glu693Asp).
BS4
No segregation data are available for NM_181523.2:c.2079A>T.
BP4
REVEL score of 0.467 exceeds the VCEP BP4 threshold of ≤0.290.
BP5
No proband data are available demonstrating an alternative molecular basis for disease.
BP7
The VCEP BP7_Supporting rule applies to synonymous and intronic variants, not missense variants.
N/A · 9
PM1 · PM5 · PM6 · PP2 · PP5 · BS2 · BP1 · BP2 · BP6
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links