Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
This variantScenario
BenignPathogenic
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
About PIK3R1
PIK3R1 encodes p85α, the regulatory subunit of phosphoinositide 3-kinase (PI3K), an enzyme complex that produces signaling molecules controlling cell growth, proliferation, and survival. The protein normally stabilizes and inhibits the PI3K catalytic subunit and helps the complex respond to signals from cell-surface receptors, including insulin, so alterations in this gene are associated with insulin resistance. PIK3R1 acts as a tumor suppressor: mutations that disrupt its inhibitory function can lead to abnormally active PI3K/AKT signaling and are found in several cancers, most often glioblastoma, as well as endometrial, breast, and colorectal cancers.
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01The reasoning
How it was classified
The recorded framework is ClinGen PIK3R1 VCEP v1.0. 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.
Met (Very Strong): out-of-frame 25-nt deletion creates a premature stop (p.His450GlnfsTer22) within the VCEP c.917-c.1890 window, predicted to trigger nonsense-mediated decay.
PM2Supporting
PM2 · supporting
Met (Supporting): absent from gnomAD v4.1, below the VCEP <0.00000132 allele-frequency threshold.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
PVS1 Very Strong (+8) plus PM2 Supporting (+1) totals 9 points, meeting the PIK3R1 VCEP Rule 2 threshold (6-9 points) for Likely Pathogenic.
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.
ACMG/AMP criteria under ClinGen PIK3R1 VCEP v1.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 2 not met · 8 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 applied at Very Strong strength: frameshift variant c.1350_1374del (p.His450GlnfsTer22) falls within the CSPEC-defined c.917-c.1890 NMD-predicted window, in exon 11, present in all 3 biologically-relevant PIK3R1 transcripts, with no applicable CSPEC exception.
PM4 not applicable: variant is a frameshift, not an in-frame indel or stop-loss, and PM4 is explicitly mutually exclusive with PVS1 per the CSPEC.
BP3 not applicable: PIK3R1 CSPEC designates BP3 as Not Applicable for this gene, and the variant's frameshift/truncating nature is not the in-frame repeat-region context BP3 addresses.
This is NM_181523.2:c.1350_1374del, NP_852664.1:p.(His450GlnfsTer22), a frameshift deletion, not a missense substitution.
The governing PIK3R1 Antibody Deficiencies VCEP specification (cspec, v1.0) explicitly marks PM1, PP2, and BP1 as Not Applicable for this gene.
PS1 and PM5 are gene-specific rules restricted by the VCEP to missense (same-codon comparator) or canonical-splice comparator scenarios; a frameshift deletion with no predicted splice impact (SpliceAI max delta 0.00) does not meet either pathway, and the dedicated pm5_candidates.json artifact confirms this variant is ineligible for the classic same-residue missense PM5 search.
All five codon/residue/domain criteria in this group are therefore not_applicable for this variant.
PIK3R1 is governed by the ClinGen Antibody Deficiencies VCEP specification v1.0, which defines PS3/BS3 exclusively via variant-specific in vitro functional assay results (lipid kinase activity, AKT kinase activity, protein binding, conformational dynamics, T-cell pS6/pAKT enrichment) or animal model data.
No functional assay or animal model evidence specific to c.1350_1374del (p.H450Qfs*22) was found in the case evidence bundle or the three full-text papers reviewed (PMID:25133428, PMID:25284480, PMID:25488983), all of which characterize different PIK3R1 variants (splice-site mutations and other missense/nonsense variants).
Both PS3 and BS3 are therefore not_assessed rather than not_met, since the gap is absence of applicable data rather than a negative/inconclusive result.
NM_181523.2:c.1350_1374del deletes 25 nucleotides (not a multiple of 3), producing a frameshift transcript predicted to encode p.(His450GlnfsTer22). This variant class (frameshift indel) is not covered by any of the PIK3R1 Antibody Deficiencies VCEP's PP3/BP4/BP7 rules, which are scoped to missense variants (REVEL/CADD) and missense/synonymous/intronic variants (SpliceAI) for PP3/BP4, and synonymous/intronic variants only for BP7.
SpliceAI was independently queried for this variant and returned max delta score = 0.00 across donor/acceptor gain/loss, indicating no predicted cryptic splice alteration; this confirms the variant behaves as a straightforward coding frameshift rather than a splice-disrupting event, but does not itself confer PP3/BP4/BP7 eligibility given the VCEP's variant-class restrictions.
REVEL/CADD were not computed because this is not an SNV (evidence.json marks revel as skipped, reason 'not snv or no coords'), so the missense in-silico path is also inapplicable.
No criteria match.
Met · 2
PVS1Very strongMet (Very Strong): out-of-frame 25-nt deletion creates a premature stop (p.His450GlnfsTer22) within the VCEP c.917-c.1890 window, predicted to trigger nonsense-mediated decay.
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Reasoning
NM_181523.2:c.1350_1374del is a 25-nucleotide (non-multiple-of-3) deletion producing a frameshift, NP_852664.1:p.(His450GlnfsTer22). The PIK3R1 VCEP CSPEC (Antibody Deficiencies Expert Panel v1.0) PVS1 Very Strong rule states: 'If a nonsense or frameshift variant introduces a premature stop codon between c.917 and c.1890, which is predicted to trigger nonsense mediated decay, and the exon is present in all 3 biologically-relevant transcripts (NM_181523.3, NM_181504.4, and NM_181524.2), apply PVS1.' The variant's coding position (c.1350) and resulting premature termination codon fall squarely within this c.917-c.1890 window. VariantValidator confirms the deletion maps to exon 11 (NC_000005.9/NC_000005.10/NG_012849.2 all report start_exon=end_exon=11), well upstream of the final exon of the ~16-exon PIK3R1 transcript (per CSPEC domain-exon mapping, nSH2 spans exons 9/11, iSH2 exons 13/14, cSH2 exons 15/16), so the resulting PTC at residue ~471 is far from the last exon-exon junction and is predicted to trigger NMD. The CSPEC's sole exception excluding PVS1 application applies only to premature stops between c.4 and c.916 (exon present only in the MANE transcript NM_181523.3 and absent from NM_181504.4/NM_181524.2, associated with recessive agammaglobulinemia 7) -- this variant's c.1350 position is outside that excluded range, so the exception does not apply. Gene-level PVS1 gate is eligible: germline LOF is an established mechanism for PIK3R1-related immunodeficiency and SHORT syndrome (autosomal dominant), per the CSPEC itself providing PVS1 guidance. No canonical splice or initiation-codon caveats apply (this is a frameshift indel, not a splice or start-codon variant). SpliceAI predicts no additional splice disruption (max delta 0.00), consistent with straightforward frameshift/NMD interpretation. PVS1 is applied at full (Very Strong) strength per the VCEP-specified default rule.
Rule
PIK3R1 VCEP CSPEC v1.0 PVS1 Very Strong: premature stop codon (nonsense/frameshift) between c.917 and c.1890 predicted to trigger NMD, in an exon present in all 3 biologically-relevant transcripts (NM_181523.3, NM_181504.4, NM_181524.2).
Evidence considered
CSPEC PVS1 Very Strong rule: premature stop codon between c.917 and c.1890 predicted to trigger NMD, with the exon present in all 3 biologically-relevant PIK3R1 transcripts, warrants PVS1 at default (Very Strong) strength.
VariantValidator exonic position mapping places the deletion in exon 11 for GRCh37, GRCh38, and RefSeqGene (NG_012849.2) coordinate systems.
pvs1_gene_context.json confirms PVS1 gene-level gate is 'eligible' because the CSPEC provides official PVS1 guidance for PIK3R1, establishing germline loss-of-function as a disease mechanism for PIK3R1-related immunodeficiency and SHORT syndrome (MONDO:1060136).
pvs1_variant_assessment.json classifies the variant as consequence_class 'frameshift' with predicted protein change p.(His450GlnfsTer22), consistent with a truncating variant subject to PVS1 evaluation.
SpliceAI shows no significant splice-altering signal (max delta score 0.00), so no competing/alternative splice interpretation displaces the frameshift/NMD prediction.
Still missing
No RNA/transcript-level NMD confirmation (e.g., patient RNA-seq) was available for this specific variant; classification relies on the CSPEC's positional/NMD-prediction rule rather than direct experimental confirmation.
No literature source specifically discusses this exact frameshift variant (H450Qfs*22); all supporting literature in this case packet concerns unrelated splice-site variants in PIK3R1 and was not used to ground this PVS1 call.
PM2SupportingMet (Supporting): absent from gnomAD v4.1, below the VCEP <0.00000132 allele-frequency threshold.
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Reasoning
The PIK3R1 VCEP applies PM2 only at supporting strength when the total allele frequency is <0.00000132 across all populations in gnomAD v4.1. The variant is absent from gnomAD v4.1, satisfying this ultra-rare population-frequency requirement. It is also absent from gnomAD v2.1 and gnomAD-Canada v1.0, providing concordant population observations; the VCEP gnomAD v4.1 rule remains the governing criterion.
Rule
PM2 Supporting: applicable when total allele frequency is <0.00000132 across all populations in gnomAD v4.1, using the VCEP parameters of prevalence 1 in 4000, allelic heterogeneity 1, genetic heterogeneity 1, and penetrance 0.95.
Evidence considered
The PIK3R1 VCEP PM2 rule requires total allele frequency <0.00000132 across all populations in gnomAD v4.1 and limits PM2 to supporting strength.
The queried NM_181523.2:c.1350_1374del / GRCh38 deletion is absent from gnomAD v4.1, so its recorded total allele frequency is below the specified threshold.
The same variant is also absent from gnomAD v2.1 and gnomAD-Canada v1.0.
The VCEP notes that population data for indels may be poorly called by next-generation sequencing; this is a residual technical caveat, but the direct gnomAD v4.1 query returned an absent result and the case includes concordant absence in additional population datasets.
BA1Not met: absent from gnomAD v4.1, below the BA1 >=0.00316 allele-frequency threshold.
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Reasoning
The PIK3R1 VCEP specifies BA1 at stand-alone strength when the gnomAD v4.1 GrpMax filtering allele frequency is at least 0.00316, or when the maximum major-continental-population allele frequency reaches that threshold if GrpMax is unavailable. The variant is absent from gnomAD v4.1, so the BA1 threshold is not met.
Rule
BA1 Stand Alone: applicable when gnomAD v4.1 GrpMax filtering allele frequency is >=0.00316; if GrpMax is unavailable, use the maximum allele frequency among the five specified major continental populations.
Evidence considered
The PIK3R1 VCEP BA1 rule sets a cutoff of GrpMax filtering allele frequency >=0.00316 in gnomAD v4.1.0.
The queried NM_181523.2:c.1350_1374del / GRCh38 deletion is absent from gnomAD v4.1; therefore its observed allele frequency is not at or above the BA1 cutoff.
BS1Not met: absent from gnomAD v4.1, below the BS1 >=0.000316 allele-frequency threshold.
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Reasoning
The PIK3R1 VCEP specifies BS1 at strong strength when the gnomAD v4.1 GrpMax filtering allele frequency is at least 0.000316, or when the maximum major-continental-population allele frequency reaches that threshold if GrpMax is unavailable. The variant is absent from gnomAD v4.1, so the BS1 threshold is not met.
Rule
BS1 Strong: applicable when gnomAD v4.1 GrpMax filtering allele frequency is >=0.000316; if GrpMax is unavailable, use the maximum allele frequency among the five specified major continental populations.
Evidence considered
The PIK3R1 VCEP BS1 rule sets a cutoff of GrpMax filtering allele frequency >=0.000316 in gnomAD v4.1.0.
The queried NM_181523.2:c.1350_1374del / GRCh38 deletion is absent from gnomAD v4.1; therefore its observed allele frequency is not at or above the BS1 cutoff.
PS2Not assessed: no proband-level parental testing, maternity/paternity confirmation, or family-history data were available.
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Reasoning
The PIK3R1 VCEP requires confirmed maternity and paternity, no family history of disease, and assessment of proband phenotype consistency using the VCEP PS4 phenotype-point framework. The case-evidence bundle contains no proband-level parental testing, maternity/paternity confirmation, family-history statement, or phenotype-point assessment for this variant; therefore PS2 cannot be adjudicated.
Rule
PIK3R1 VCEP PS2: both maternity and paternity must be confirmed, with no family history of disease; strength is selected using the VCEP de novo point-counting framework based on proband phenotype consistency.
Evidence considered
The governing PIK3R1 VCEP specifies that PS2 requires both maternity and paternity to be confirmed and no family history of disease.
The consolidated case-evidence bundle provides variant normalization and population/database results but does not provide parental genotypes, trio testing, family history, or a proband phenotype-point score.
Still missing
Documented parental testing results for the variant
Confirmation of both maternity and paternity
Explicit absence or presence of a family history of the relevant disease
Proband phenotype details and VCEP PS4 phenotype-point score
Assessment of PIK3CD testing where required for phenotype-consistency selection
PS3Not assessed: no functional assay data (kinase activity, protein binding, animal models) for this exact variant were available.
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Reasoning
The PIK3R1 VCEP (Antibody Deficiencies) specification defines PS3 based on abnormal results in approved in vitro assays (lipid kinase activity, AKT kinase activity, protein binding, conformational dynamics; PMIDs 28167755, 23810379, 25133428, 25488983) or the pS6/pAKT T-cell enrichment ratio assay (PMID:40543502), or animal model data (PMID 26974159, PMID 28632845). None of the three full-text papers retrieved for this case (PMID:25133428, PMID:25284480, PMID:25488983) report functional assay data for the specific variant c.1350_1374del (p.H450Qfs*22) -- these papers characterize different PIK3R1 splice-site and missense variants. No source in this case's evidence bundle contains functional assay results (kinase activity, protein binding, conformational dynamics, T-cell pS6/pAKT enrichment, or animal model) for this exact frameshift variant. The variant is also absent from ClinVar, gnomAD, and COSMIC, and no VCEP functional-assay spreadsheet excerpt for this variant was captured in the bundle.
Still missing
No functional assay (kinase activity, protein binding, conformational dynamics, or T-cell pS6/pAKT enrichment) has been performed or reported for c.1350_1374del (p.H450Qfs*22) in the sources reviewed.
The PIK3R1_Functional_Assays_PS3_BS3.xlsx VCEP spreadsheet was identified as an available gene resource but its variant-level contents were not captured in this case's evidence bundle, so it could not be checked for a variant-specific entry.
No animal model data for this variant were identified.
PS4Not assessed: no proband phenotype scoring, case-control enrichment data, or unrelated affected individuals carrying this variant were available.
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Reasoning
PS4 was not assessed because the case-evidence bundle contains no proband-level phenotype scoring, case-control enrichment data, or documented unrelated affected individuals carrying the exact variant NM_181523.2:c.1350_1374del. The PIK3R1 VCEP requires at least one qualifying proband with at least 6 phenotype points and testing that excludes a pathogenic or likely pathogenic PIK3CD variant for PS4_Supporting; stronger levels require two to three or at least four qualifying probands. No such evidence is available in the bundle.
Rule
PIK3R1 VCEP PS4: count only probands meeting the phenotype scoring rubric and required negative PIK3CD testing; one, two to three, or four or more qualifying probands correspond to Supporting, Moderate, or Strong strength respectively.
Evidence considered
The governing ClinGen Antibody Deficiencies PIK3R1 specification defines PS4_Supporting as one qualifying proband, PS4_Moderate as two to three qualifying probands, and PS4 as four or more qualifying probands; each proband must meet the specified phenotype-point and PIK3CD-testing requirements.
The case bundle reports no exact ClinVar record for NM_181523.2:c.1350_1374del and provides no proband-level phenotype or case-control evidence for this exact variant.
Still missing
Qualifying proband-level phenotype features and PS4 Table 3 point scores are not provided.
The required exclusion of an alternative pathogenic or likely pathogenic PIK3CD variant is not documented for any proband.
No exact-variant case series or statistically evaluable case-control enrichment is available.
PP1Not assessed: no affected relatives, pedigree, segregation results, or meiosis counts were available.
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Reasoning
The PIK3R1 VCEP requires affected relatives to meet at least 6 points in the PS4 phenotype-scoring rubric and defines PP1 strength by the number of affected meioses. The case-evidence bundle contains no affected relatives, variant-positive relatives, pedigree, segregation results, or meiosis count; therefore PP1 cannot be applied or excluded from the available evidence.
Rule
PIK3R1 VCEP PP1: each affected family member must reach at least 6 PS4 phenotype points; Supporting requires one affected first-degree relative (1 meiosis), Moderate requires the specified 2-meiosis configurations, and Strong requires at least 4 meioses; do not apply if BA1 or BS1 is met.
Evidence considered
The governing PIK3R1 VCEP defines PP1 Supporting as co-segregation across the proband and one affected first-degree relative, PP1 Moderate as two specified meiosis configurations, and PP1 Strong as at least four meioses.
The consolidated case-evidence bundle contains no family segregation observations or affected-relative phenotype assessments for this variant.
Still missing
Pedigree and relationship of each tested family member
Variant status for affected and unaffected relatives
Phenotype documentation and PS4 score of each potentially affected relative
Number of informative affected meioses
Population evidence review sufficient to confirm that BS1 or BA1 does not preclude PP1
PP4Not assessed: no qualifying proband with at least 10 VCEP phenotype points or documented exclusion of an alternative PIK3CD variant.
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Reasoning
PP4 was not assessed because the case-evidence bundle does not provide a qualifying proband with at least 10 PIK3R1 VCEP phenotype points and documented genotyping that excluded an alternative pathogenic or likely pathogenic PIK3CD variant. The bundle also lacks the patient-level phenotype and family-history details needed to establish a highly specific phenotype.
Rule
PIK3R1 VCEP PP4: at least 10 phenotype points plus genotyping that does not identify an alternative PIK3CD basis; PP4_Moderate additionally requires abnormal patient cell-based PI3K-delta pathway activity, and the proband cannot also be counted for PS4.
Evidence considered
The governing PIK3R1 VCEP requires at least 10 phenotype points and exclusion of an alternative PIK3CD molecular basis for PP4_Supporting; PP4_Moderate additionally requires patient cell-based evidence of abnormally high disease-relevant PI3K-delta pathway activity.
The consolidated bundle contains no qualifying proband phenotype score, PIK3CD exclusion result, or patient cell-based pathway result for this exact variant.
Still missing
A qualifying proband with at least 10 phenotype points is not documented.
Negative PIK3CD testing for the relevant proband is not documented.
No patient-level phenotype or family-history record is available to evaluate phenotype specificity.
BS3Not assessed: no normal-result functional assay data for this exact variant were available.
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Reasoning
The PIK3R1 VCEP specification defines BS3 based on normal (non-damaging) results in the same approved assay classes used for PS3 (lipid kinase activity, AKT kinase activity, protein binding, conformational dynamics; PMIDs 28167755, 23810379, 25133428, 25488983) or the pS6/pAKT T-cell enrichment ratio assay (PMID:40543502), or animal model data failing to recapitulate phenotype. None of the three full-text papers retrieved for this case (PMID:25133428, PMID:25284480, PMID:25488983) report functional assay data for c.1350_1374del (p.H450Qfs*22); they characterize other PIK3R1 variants. No source in the evidence bundle contains a normal/non-damaging functional assay result for this exact variant.
Still missing
No functional assay evidence (normal or abnormal) has been identified for c.1350_1374del (p.H450Qfs*22) in the sources reviewed.
The VCEP PIK3R1_Functional_Assays_PS3_BS3.xlsx spreadsheet's variant-level contents were not captured in this case's evidence bundle.
BS4Not assessed: no pedigree or affected family members lacking the variant were available.
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Reasoning
The PIK3R1 VCEP requires affected family members lacking the variant to reach at least 6 points in the PS4 phenotype-scoring rubric. BS4 Supporting requires one such affected non-carrier and BS4 Strong requires at least two. The case-evidence bundle contains no pedigree, affected non-carrier, genotype, or phenotype-scoring data; therefore BS4 cannot be adjudicated.
Rule
PIK3R1 VCEP BS4: use caution when phenotype specificity is limited; each affected family member lacking the variant must reach at least 6 PS4 points; one qualifying affected non-carrier supports BS4 Supporting and at least two support BS4 Strong.
Evidence considered
The governing PIK3R1 VCEP defines BS4 Supporting when one affected family member lacking the variant reaches at least 6 PS4 phenotype points and BS4 Strong when at least two do so.
The consolidated case-evidence bundle contains no affected family-member non-segregation observations or qualifying phenotype scores.
Still missing
Identification of affected relatives tested for the variant
Variant-negative genotype results in affected relatives
Phenotype documentation and PS4 score of each affected non-carrier
Evaluation for phenocopies or alternative molecular explanations
BP5Not assessed: no documented cases where this variant coexisted with an alternative molecular cause of disease were available.
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Reasoning
BP5 was not assessed because the case-evidence bundle does not document at least two cases in which the exact variant was observed with an alternative molecular basis for disease. The PIK3R1 VCEP requires at least two such cases when relying on assertions involving genes outside the VCEP's purview.
Rule
PIK3R1 VCEP BP5_Supporting: require at least two cases with the exact variant and an alternative molecular basis for disease when the alternative gene is outside the VCEP's purview.
Evidence considered
The governing PIK3R1 VCEP BP5 rule requires at least two cases with an alternative molecular basis for disease to mitigate reliance on assertions involving genes outside the Antibody Deficiencies VCEP's purview.
The case bundle contains no exact-variant ClinVar record and no documented cases with an alternative molecular diagnosis.
Still missing
No qualifying case carrying the exact variant with an alternative molecular diagnosis is documented.
The required minimum of two cases with an alternative molecular basis is not met or assessable from the bundle.
The alternative diagnoses, testing methods, and phase/interpretation context are not provided.
Not applicable · 16· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: frameshift deletion, not a missense or canonical splice variant, so no same-codon comparator pathway exists.
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Reasoning
NM_181523.2:c.1350_1374del is a frameshift deletion (NP_852664.1:p.(His450GlnfsTer22)), not a missense or canonical splice-site variant. The PIK3R1 Antibody Deficiencies VCEP PS1 specification applies only to (1) missense variants compared to another missense variant at the same codon previously classified Pathogenic without using PS1, or (2) canonical splice variants compared to a previously classified splice variant with matching predicted splicing impact. Neither scenario applies to a frameshift deletion, and SpliceAI/Pangolin predict no splice impact for this variant (max delta score 0.00), so there is no splicing-based comparator pathway either.
Rule
PIK3R1 VCEP PS1 (Antibody Deficiencies Expert Panel v1.0): applies to missense variants at a codon matching a prior PS1-free Pathogenic missense classification, or to canonical splice variants matching prior splice-impact classifications.
Evidence considered
VCEP PS1 rule (cspec) restricts PS1 to missense variants (same-codon amino-acid comparator) or canonical splice variants (matching predicted splicing disruption compared to a prior P/LP splice variant); it does not extend to frameshift/indel variants.
This variant is a 25-nt in-frame-irrelevant deletion causing a frameshift, p.(His450GlnfsTer22), not an amino-acid substitution at a single codon.
case_summary.json compact_evidence.spliceai reports max_delta_score = 0.00, so there is no basis to invoke the PS1 splice-variant comparator pathway either.
PM1VCEPNot applicable: the PIK3R1 VCEP defines no mutational hotspot rule for PM1.
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Reasoning
The PIK3R1 Antibody Deficiencies VCEP specification explicitly marks PM1 as Not Applicable for this gene (no mutational hotspot/critical functional domain rule was defined by the VCEP for PM1). No generic ACMG fallback is warranted since a gene-specific VCEP specification (cspec) governs this gene and explicitly addresses PM1 applicability.
VCEP rule
PIK3R1 VCEP: PM1 explicitly not applicable.
Evidence considered
case_summary.json compact_evidence.cspec lists PM1 with "applicability": "Not Applicable" for the PIK3R1 Antibody Deficiencies VCEP specification v1.0.
PM3VCEPNot applicable: PM3 is reserved for recessive disorders, and PIK3R1-related disease is autosomal dominant.
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Reasoning
The applicable ClinGen Antibody Deficiencies Expert Panel specification for PIK3R1 designates PM3 as not applicable because PM3 is specific to recessive disorders. The governing framework describes PIK3R1-related immunodeficiency and SHORT syndrome as autosomal dominant; therefore, phase or trans-observation evidence cannot be used to apply PM3 in this case.
VCEP rule
PM3 is not applicable for PIK3R1-related immunodeficiency under the governing VCEP specification because the code is specific to recessive disorders.
Evidence considered
The PIK3R1 VCEP specification states: "Not applicable, as this code is specific to recessive disorders."
The same specification identifies the relevant disease context as autosomal dominant inheritance.
PM4N/ANot applicable: 25-nucleotide deletion is out-of-frame, not an in-frame indel, and PM4 is mutually exclusive with PVS1.
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Reasoning
PM4 under the PIK3R1 CSPEC applies only to in-frame deletions/insertions causing a protein length change of >=2 amino acids (with a conservation requirement) or stop-loss variants adding >=2 C-terminal residues. NM_181523.2:c.1350_1374del removes 25 nucleotides, which is not a multiple of 3, so it causes a frameshift rather than an in-frame deletion; it is also not a stop-loss variant. PM4 therefore does not apply to this variant type. In addition, the CSPEC explicitly states PM4 'is mutually exclusive with PVS1,' and PVS1 has been applied at Very Strong strength for this variant, further precluding PM4.
Rule
PIK3R1 VCEP CSPEC v1.0 PM4: applies to in-frame deletion/insertion (>=2 aa length change, conserved) or stop-loss (>=2 added C-terminal aa) variants only; mutually exclusive with PVS1.
Evidence considered
CSPEC PM4 rule requires an in-frame deletion/insertion (protein length change >=2 aa with conservation criteria) or a stop-loss variant, and explicitly states PM4 is mutually exclusive with PVS1.
pvs1_variant_assessment.json classifies this variant as a frameshift (25 nt deletion, not a multiple of 3), so it does not meet the in-frame deletion/insertion structural requirement for PM4.
PM5N/ANot applicable: frameshift deletion, not a missense change, so no same-codon missense comparator applies.
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Reasoning
The PIK3R1 VCEP PM5 rule requires a missense variant encoding a different amino acid change at the same codon as a variant previously classified Pathogenic or Likely Pathogenic by the VCEP (without using PM5 for that comparator), with a Grantham-score and splicing-neutrality comparison. This case is a frameshift deletion (p.His450GlnfsTer22), not a missense substitution, so there is no single altered residue to compare against same-codon missense comparators. The dedicated PM5 candidate-search artifact for this case confirms the variant consequence class is frameshift, not missense, and explicitly found the classic same-residue missense PM5 pathway inapplicable with zero comparator candidates identified.
Rule
PIK3R1 VCEP PM5 (Antibody Deficiencies Expert Panel v1.0): same-codon missense comparator required; not applicable to frameshift variants.
Evidence considered
VCEP PM5 rule (cspec) is restricted to missense variants encoding a different amino-acid change at the same codon as a prior P/LP missense comparator classified without PM5.
pm5_candidates.json artifact: eligible_for_classic_pm5_search=false, reason='Framework is classic same-residue missense PM5, but the variant consequence class (frameshift) is not missense.' total_candidates_seen=0, same_residue_candidates=0.
PM6VCEPNot applicable: the VCEP directs apparent de novo cases to PS2 instead of PM6.
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Reasoning
PM6 is explicitly designated not applicable by the governing PIK3R1 VCEP. The specification directs that an apparent de novo occurrence without confirmed maternity and paternity is handled using PS2 in lieu of PM6, not PM6.
VCEP rule
PIK3R1 VCEP PM6: not applicable; use PS2 in lieu of PM6 for assumed de novo occurrences without confirmation of maternity and paternity.
Evidence considered
The PIK3R1 VCEP marks PM6 as not applicable and states that apparent de novo occurrences without confirmed maternity and paternity use PS2 in lieu of PM6.
PP2VCEPNot applicable: the PIK3R1 VCEP marks PP2 as not applicable (missense-only rule).
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Reasoning
The PIK3R1 Antibody Deficiencies VCEP specification explicitly marks PP2 as Not Applicable for this gene. This is also consistent with the variant being a frameshift deletion rather than a missense substitution, to which PP2 (missense-intolerant gene, low benign-missense rate) would not classically apply regardless of gene-level missense constraint.
VCEP rule
PIK3R1 VCEP: PP2 explicitly not applicable.
Evidence considered
case_summary.json compact_evidence.cspec lists PP2 with "applicability": "Not Applicable" for the PIK3R1 Antibody Deficiencies VCEP specification v1.0.
Variant is a frameshift deletion (p.His450GlnfsTer22), not a missense substitution, further supporting inapplicability of a missense-rate-based criterion such as PP2.
PP3N/ANot applicable: PP3 covers missense, synonymous, or intronic variants only; this is a frameshift deletion.
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Reasoning
NM_181523.2:c.1350_1374del is a 25-nucleotide exonic deletion producing a frameshift (NP_852664.1:p.(His450GlnfsTer22)), not a missense, synonymous, intronic, or small in-frame indel. The PIK3R1 Antibody Deficiencies VCEP PP3 rule is explicitly scoped to those variant classes only (missense variants via REVEL>=0.644 + CADD>=26.0, or missense/synonymous/intronic variants via SpliceAI damaging prediction outside +/-1,2 dinucleotide positions). Since 25 nt is not a multiple of 3, this deletion is out-of-frame and does not qualify as the 'small in-frame insertion and/or deletion' category the VCEP requires splice assessment for either. SpliceAI was nonetheless run and showed no splice impact (max delta score = 0.00), confirming this variant acts as a coding frameshift rather than a cryptic splice-altering event, but this does not create VCEP eligibility for PP3 given the variant class exclusion.
Rule
PIK3R1 VCEP PP3: missense REVEL>=0.644 & CADD>=26.0; or missense/synonymous/intronic with SpliceAI damaging delta>=0.2 outside +/-1,2 dinucleotide positions
Evidence considered
SpliceAI Lookup (NM_181523.2:c.1350_1374del) reports max delta score = 0.00 across all four splice-altering categories (donor gain, donor loss, acceptor gain, acceptor loss), indicating no predicted splice impact.
PIK3R1 ClinGen Antibody Deficiencies VCEP specification v1.0 PP3 rule restricts application to missense variants (REVEL/CADD thresholds) or missense/synonymous/intronic variants assessed by SpliceAI; frameshift deletions are not a listed eligible variant class.
REVEL/CADD scoring was not computed for this variant because it is not an SNV (evidence.json: revel skipped, reason 'not snv or no coords').
PP5VCEPNot applicable: the VCEP disallows PP5, and this variant is absent from ClinVar.
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Reasoning
PP5 is not applicable under the governing PIK3R1 VCEP specification, which states that PP5 is not for use. Independently, the case bundle reports that this exact variant is absent from ClinVar, so there is no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion that could satisfy the requested PP5 gate.
VCEP rule
Do not use PP5 for PIK3R1 under the governing VCEP; an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic assertion is required by the requested gate but is absent here.
Evidence considered
The PIK3R1 VCEP marks PP5 as not applicable and states that the criterion is not for use as recommended by the ClinGen SVI VCEP Review Committee.
The case bundle reports no exact ClinVar record or classification for NM_181523.2:c.1350_1374del; therefore no expert-panel Pathogenic or Likely pathogenic assertion is available.
BS2VCEPNot applicable: the VCEP excludes BS2 due to incomplete penetrance and variable expressivity.
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Reasoning
The PIK3R1 VCEP marks BS2 as not applicable because of incomplete penetrance and variable expressivity of the disease. This gene-specific restriction takes precedence over generic ACMG/AMP use of observations in healthy adults.
VCEP rule
BS2 is not applicable under the PIK3R1 VCEP because of incomplete penetrance and variable expressivity.
Evidence considered
The PIK3R1 VCEP BS2 instruction states that BS2 does not apply due to incomplete penetrance and variable expressivity of disease.
BP1VCEPNot applicable: the VCEP marks BP1 as not applicable (missense-only rule).
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Reasoning
The PIK3R1 Antibody Deficiencies VCEP specification explicitly marks BP1 as Not Applicable for this gene. This is also consistent with the variant being a frameshift deletion rather than a missense substitution, to which BP1 (missense variant in a gene where truncating variants cause disease) would not classically apply as a benign-missense argument.
VCEP rule
PIK3R1 VCEP: BP1 explicitly not applicable.
Evidence considered
case_summary.json compact_evidence.cspec lists BP1 with "applicability": "Not Applicable" for the PIK3R1 Antibody Deficiencies VCEP specification v1.0.
Variant is a frameshift deletion, not a missense substitution, further supporting inapplicability of BP1.
BP2VCEPNot applicable: the VCEP disallows BP2 because allelic mechanisms for PIK3R1 are incompletely understood.
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Reasoning
The applicable ClinGen Antibody Deficiencies Expert Panel specification explicitly instructs that BP2 must not be used for PIK3R1. It states that BP2 is not applicable because the field does not currently understand all potential allelic mechanisms associated with PIK3R1 variants and diverse combinatorial variant effects cannot be excluded.
VCEP rule
BP2 is not applicable for PIK3R1 under the governing VCEP specification and must not be used.
Evidence considered
The PIK3R1 VCEP specification states: "Do not use this criterion."
The specification explains that BP2 is not applicable because potential diverse combinatorial allelic effects in PIK3R1 cannot be excluded.
BP3VCEPNot applicable: BP3 applies to in-frame indels in repeat regions; this is an out-of-frame deletion.
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Reasoning
The PIK3R1 VCEP CSPEC v1.0 explicitly designates BP3 as 'Not Applicable' for this gene, with no strength rules provided. This variant is also a frameshift/truncating indel rather than an in-frame deletion/insertion in a repeat region, so BP3 (in-frame indel in a repetitive region without a known function) would not be structurally relevant even under a generic ACMG fallback.
VCEP rule
PIK3R1 VCEP CSPEC v1.0: BP3 applicability = Not Applicable.
Evidence considered
CSPEC lists BP3 with 'applicability': 'Not Applicable' for PIK3R1, so this criterion is not used under the governing VCEP specification.
The variant is a frameshift deletion (not an in-frame indel), so BP3's structural prerequisite (in-frame indel in a repeat/no-known-function region) is not met regardless of applicability status.
BP4N/ANot applicable: BP4 covers missense, synonymous, or intronic variants only; this is a frameshift deletion.
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Reasoning
This variant is a 25-nt out-of-frame deletion (frameshift), not a missense, synonymous, or intronic variant, so it falls outside the PIK3R1 VCEP's BP4 applicability categories (missense REVEL<=0.290 & CADD<=21.5 with SpliceAI deltas <0.1; or synonymous/intronic with SpliceAI deltas <0.1). SpliceAI itself shows no predicted splice disruption (max delta = 0.00), but this observation does not create BP4 eligibility for a frameshift-class variant under this VCEP's rule, which is written for missense/synonymous/intronic variants only.
Rule
PIK3R1 VCEP BP4: missense REVEL<=0.290 & CADD<=21.5 with SpliceAI deltas <0.1; or synonymous/intronic with SpliceAI deltas <0.1
Evidence considered
SpliceAI Lookup shows max delta score = 0.00, below the <0.1 BP4 threshold, but the VCEP BP4 rule only extends this SpliceAI-based path to missense, synonymous, or intronic variants, none of which describe this frameshift deletion.
REVEL/CADD not computed (variant is not an SNV), so the missense REVEL/CADD arm of BP4 is also inapplicable.
BP6VCEPNot applicable: the VCEP disallows BP6, and this variant is absent from ClinVar.
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Reasoning
BP6 is not applicable under the governing PIK3R1 VCEP specification, which states that BP6 is not for use. In addition, the exact variant is absent from ClinVar, so there is no exact-variant ClinVar expert-panel Benign or Likely benign assertion satisfying the requested BP6 gate.
VCEP rule
Do not use BP6 for PIK3R1 under the governing VCEP; an exact-variant ClinVar expert-panel Benign/Likely benign assertion is required by the requested gate but is absent here.
Evidence considered
The PIK3R1 VCEP marks BP6 as not applicable and states that the criterion is not for use as recommended by the ClinGen SVI VCEP Review Committee.
The case bundle reports no exact ClinVar record or classification for NM_181523.2:c.1350_1374del; therefore no expert-panel Benign or Likely benign assertion is available.
BP7N/ANot applicable: BP7 applies to synonymous or intronic variants only; this is an exonic frameshift deletion.
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Reasoning
BP7 under the PIK3R1 VCEP specification applies only to synonymous variants (outside the first exonic nucleotide/last 3 nucleotides) or intronic variants (outside +1 to +6/-1 to -20) with SpliceAI deltas <0.1. This variant is a 25-nucleotide exonic frameshift deletion, not synonymous or intronic, so BP7 does not apply regardless of the SpliceAI result.
Rule
PIK3R1 VCEP BP7: synonymous or intronic variant with all SpliceAI deltas <0.1
Evidence considered
Variant is an exonic frameshift deletion (p.(His450GlnfsTer22)), not a synonymous or intronic substitution, which are the only variant classes the PIK3R1 VCEP BP7 rule covers.
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—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele 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
Pangolin splice lossmagnitude shown
-0.055
Pangolin splice gain
0.008
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3N/ANot applicable: PP3 covers missense, synonymous, or intronic variants only; this is a frameshift deletion.
Details ▾Hide ▴
Reasoning
NM_181523.2:c.1350_1374del is a 25-nucleotide exonic deletion producing a frameshift (NP_852664.1:p.(His450GlnfsTer22)), not a missense, synonymous, intronic, or small in-frame indel. The PIK3R1 Antibody Deficiencies VCEP PP3 rule is explicitly scoped to those variant classes only (missense variants via REVEL>=0.644 + CADD>=26.0, or missense/synonymous/intronic variants via SpliceAI damaging prediction outside +/-1,2 dinucleotide positions). Since 25 nt is not a multiple of 3, this deletion is out-of-frame and does not qualify as the 'small in-frame insertion and/or deletion' category the VCEP requires splice assessment for either. SpliceAI was nonetheless run and showed no splice impact (max delta score = 0.00), confirming this variant acts as a coding frameshift rather than a cryptic splice-altering event, but this does not create VCEP eligibility for PP3 given the variant class exclusion.
Rule
PIK3R1 VCEP PP3: missense REVEL>=0.644 & CADD>=26.0; or missense/synonymous/intronic with SpliceAI damaging delta>=0.2 outside +/-1,2 dinucleotide positions
Evidence considered
SpliceAI Lookup (NM_181523.2:c.1350_1374del) reports max delta score = 0.00 across all four splice-altering categories (donor gain, donor loss, acceptor gain, acceptor loss), indicating no predicted splice impact.
PIK3R1 ClinGen Antibody Deficiencies VCEP specification v1.0 PP3 rule restricts application to missense variants (REVEL/CADD thresholds) or missense/synonymous/intronic variants assessed by SpliceAI; frameshift deletions are not a listed eligible variant class.
REVEL/CADD scoring was not computed for this variant because it is not an SNV (evidence.json: revel skipped, reason 'not snv or no coords').
BP4N/ANot applicable: BP4 covers missense, synonymous, or intronic variants only; this is a frameshift deletion.
Details ▾Hide ▴
Reasoning
This variant is a 25-nt out-of-frame deletion (frameshift), not a missense, synonymous, or intronic variant, so it falls outside the PIK3R1 VCEP's BP4 applicability categories (missense REVEL<=0.290 & CADD<=21.5 with SpliceAI deltas <0.1; or synonymous/intronic with SpliceAI deltas <0.1). SpliceAI itself shows no predicted splice disruption (max delta = 0.00), but this observation does not create BP4 eligibility for a frameshift-class variant under this VCEP's rule, which is written for missense/synonymous/intronic variants only.
Rule
PIK3R1 VCEP BP4: missense REVEL<=0.290 & CADD<=21.5 with SpliceAI deltas <0.1; or synonymous/intronic with SpliceAI deltas <0.1
Evidence considered
SpliceAI Lookup shows max delta score = 0.00, below the <0.1 BP4 threshold, but the VCEP BP4 rule only extends this SpliceAI-based path to missense, synonymous, or intronic variants, none of which describe this frameshift deletion.
REVEL/CADD not computed (variant is not an SNV), so the missense REVEL/CADD arm of BP4 is also inapplicable.
BP7N/ANot applicable: BP7 applies to synonymous or intronic variants only; this is an exonic frameshift deletion.
Details ▾Hide ▴
Reasoning
BP7 under the PIK3R1 VCEP specification applies only to synonymous variants (outside the first exonic nucleotide/last 3 nucleotides) or intronic variants (outside +1 to +6/-1 to -20) with SpliceAI deltas <0.1. This variant is a 25-nucleotide exonic frameshift deletion, not synonymous or intronic, so BP7 does not apply regardless of the SpliceAI result.
Rule
PIK3R1 VCEP BP7: synonymous or intronic variant with all SpliceAI deltas <0.1
Evidence considered
Variant is an exonic frameshift deletion (p.(His450GlnfsTer22)), not a synonymous or intronic substitution, which are the only variant classes the PIK3R1 VCEP BP7 rule covers.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
3 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
A human immunodeficiency caused by mutations in the PIK3R1 gene.
Characterizes heterozygous splice site mutations affecting the same PIK3R1 splice site in patients with hypogammaglobulinemia; describes AKT kinase activity assays used to demonstrate p85alpha regulatory subunit dysregulation, but does not test or mention c.1350_1374del (p.H450Qfs*22).
We identified 2 different heterozygous splice site mutations that affect the same splice site in PIK3R1
Abstract
Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors.
Describes neomorphic PIK3R1 cancer mutations (R348* and L370fs) that activate the MAPK pathway and confer sensitivity to MEK/JNK inhibitors; does not test or mention c.1350_1374del (p.H450Qfs*22).
the most common recurrent PIK3R1 mutation PIK3R1(R348*) and a nearby mutation PIK3R1(L370fs)
Abstract
Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.
Characterizes a heterozygous splice mutation in PIK3R1 causing human immunodeficiency via dominant PI3K activation; functional work includes AKT/S6 phosphorylation and protein binding assays, but does not test or mention c.1350_1374del (p.H450Qfs*22).
This variant was interpreted by pipeline 7.1.0.
The current version is 11.0.07.
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