NM_181523.2:c.1042del (p.Arg348GlufsTer25) is a frameshift deletion in exon 9 of PIK3R1 introducing a premature termination codon at residue 372, predicted to trigger nonsense-mediated decay.1 PVS1 is met at Very Strong strength: the PTC lies between c.917 and c.1890, is predicted to trigger NMD, and the exon 9 location satisfies the CSPEC PVS1 rule for the Antibody Deficiencies VCEP framework. Transcript presence across all three biologically relevant transcripts (NM_181523.3, NM_181504.4, NM_181524.2) should be confirmed.2 PM2_Supporting is met: the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, meeting the VCEP allele frequency threshold of <0.00000132.3 No additional pathogenic or benign criteria are met. PS3/BS3 lack variant-specific functional data. PS2/PM6 lack de novo reports. PS4/PP4 lack probands meeting VCEP phenotype criteria. PP1 lacks segregation data. PP3/BP4 are not applicable to frameshift variants. PM4 is mutually exclusive with PVS1. PM5/PS1 are not applicable to non-missense variants.4 Combined Bayesian score: PVS1 (Very Strong = 8 points) + PM2_Supporting (Supporting = 1 point) = 9 points. Under the Tavtigian 2020 Bayesian point scale adopted by the Antibody Deficiencies VCEP, a score of 6–9 points corresponds to Likely Pathogenic.5
PIK3R1
Final classification
Likely Pathogenic
PIK3R1 c.1042del · p.Arg348GlufsTer25
PIK3R1
NM_181523.2:c.1042del (p.Arg348GlufsTer25) is a frameshift deletion in exon 9 of PIK3R1 introducing a premature termination codon at residue 372, predicted to trigger nonsense-mediated decay.
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: PVS1 very strong (+8) + PM2 supporting (+1) = 9 points, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
PIK3R1 c.1042del
PVS1 + PM2
→
Likely Pathogenic
Gene diagram
· NM_181523.2 · variants mapped to exon structure
PIK3R1
NM_181523.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 10 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
review
Pathogenic
NM_181523.2:c.1042del is a frameshift deletion in exon 9 introducing a premature termination codon at residue 372 (p.Arg348GlufsTer25). The PTC lies between c.917 and c.1890 and is predicted to trigger nonsense-mediated decay. Per Antibody Deficiencies VCEP PVS1 rules, PVS1 applies at Very Strong strength if the affected exon is present in all three biologically relevant transcripts (NM_181523.3, NM_181504.4, NM_181524.2).
Frameshift deletion c.1042del in exon 9 between c.917 and c.1890PTC at codon 372 predicted to trigger NMD (termination >50-55 nt upstream of last exon-exon junction)Gene-level LOF mechanism supported by CSPEC/VCEP framework
✓
PM2
supporting
Pathogenic
The variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the VCEP PM2_Supporting allele frequency threshold of less than 0.00000132 across all populations. Used at PM2_Supporting strength per VCEP specifications.
Absent from gnomAD v2.1 (0 alleles)Absent from gnomAD v4.1 (0 alleles)Absent from gnomAD-Canada v1.0 (0 alleles)
Assessed · not applied
Pathogenic
PS2
No de novo occurrence with confirmed maternity and paternity has been reported for this variant in the reviewed literature or ClinVar submissions.
PS3
No variant-specific functional data from VCEP-approved in vitro assays (lipid kinase activity, AKT kinase activity, protein binding, conformational dynamics, or T-cell enrichment ratio) has been identified for NM_181523.2:c.1042del.
PS4
No probands meeting the VCEP phenotype scoring criteria (Table 3) with appropriate PIK3CD locus genotyping have been reported for this variant.
PP1
No co-segregation data has been reported for this variant in the reviewed literature.
PP4
No proband meeting VCEP phenotype scoring criteria (≥10 points in the PS4 counting rubric) with PIK3CD locus genotyping has been reported for this variant.
Benign
BA1
The variant is absent from gnomAD v4.1.
BS1
The variant is absent from gnomAD v4.1.
BS3
No variant-specific functional data demonstrating a non-damaging effect in VCEP-approved in vitro assays has been identified for NM_181523.2:c.1042del.
BS4
No data on lack of segregation in affected family members has been reported for this variant.
BP5
No cases with an alternative molecular basis for disease have been reported for this variant.
N/A · 16
PS1 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP3 · PP5 · BS2 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
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).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 6 PMIDs not cited in assessment
25284480 ↗
Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors.
ONCOKB
25488983 ↗
Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.
ONCOKB
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR