The PIK3CA NM_006218.2:c.2015+9A>G (NP_006209.2:p.?) variant has been reported in ClinVar, where the aggregate classification is likely benign and the ClinGen Brain Malformations Variant Curation Expert Panel has classified it as likely benign.1 This variant is present in population databases at a frequency above the Brain Malformations VCEP BS1 threshold of 0.0185%, including 31/249678 alleles in gnomAD v2.1 (AF 0.01242%) and a highest observed African/African American frequency of 0.09391% in gnomAD v4.1.2 No variant-specific functional study was identified showing either an abnormal or a normal effect on PIK3CA splicing or function.3 Available computational splicing evidence could not be independently confirmed as a complete 2-of-3 benign prediction set, so BP4 and BP7 were not applied from the available records.4
Final classification
Likely Benign
BS1BP6
PIK3CA
c.2015+9A>G
p.?
This variant
The PIK3CA NM_006218.2:c.2015+9A>G (NP_006209.2:p.?) variant has been reported in ClinVar, where the aggregate classification is likely benign and the ClinGen Brain Malformations Variant Curation Expert Panel has classified it as likely benign.
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: BS1 strong (-4) = -4 points, which maps to Likely Benign.
Classification rationale
BS1BP6
Likely Benign
PIK3CA c.2015+9A>G
BS1 + BP6
→
Likely Benign
2
gnomad_v2 ↗gnomad_v4 ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
3
cspec ↗
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.
Gene diagram
· NM_006218.2 · variants mapped to exon structure
PIK3CA
NM_006218.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 12 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
BS1
strong
review
Benign
The BS1 threshold in this VCEP is >0.0185%. This variant exceeds that threshold in gnomAD, with African/African American AF 0.08591% in v2.1 and 0.09391% in v4.1, supporting BS1.
gnomAD v2.1 African/African American AF 0.08591%gnomAD v4.1 African/African American AF 0.09391%
Assessed · not applied
· 5 not met · 7 not assessed
Pathogenic
PS2
No confirmed de novo or tissue-mosaic case data with parental testing were identified for this exact variant, so PS2 cannot be assessed from the available evidence.
PS3
No published RNA study, minigene assay, or other well-established functional assay was identified for this exact intronic variant, so PS3 cannot be applied.
PS4
No case-series or enrichment data were identified for this exact variant, and the prerequisite PM2 criterion is not met because this variant is present in gnomAD above a single-observation level.
PM1
This variant is intronic at c.2015+9 and does not alter a protein residue within the PIK3CA Table 4 critical functional domains, so PM1 is not met.
PM2
The Brain Malformations VCEP allows PM2 only for variants absent or extremely rare in controls, with one person maximum.
Benign
BA1
The BA1 threshold in this VCEP is >0.0926%.
BS2
BS2 requires at least 3 homozygotes in gnomAD or at least 3 well-phenotyped unaffected family members.
BS3
No well-established study was identified showing that this variant has no effect on splicing or downstream PIK3CA function, so BS3 cannot be applied.
BP2
No phase data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 cannot be assessed.
BP4
BP4 for this VCEP requires at least 2 of 3 splicing tools to predict no splicing impact for an intronic non-canonical variant.
BP5
No alternate molecular diagnosis was identified that would explain the phenotype independently of this variant, so BP5 cannot be assessed.
BP7
BP7 for this VCEP requires a non-canonical intronic variant at a non-conserved nucleotide with PhyloP <0.1.
N/A · 14
PVS1 · PS1 · PM3 · PM4 · PM5 · PM6 · PP1 · PP2 · PP3 · PP4 · PP5 · BS4 · BP1 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 5.80893e-05; MAF= 0.00581%, 90/1549338 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000939149; MAF= 0.09391%, 68/72406 alleles, homozygotes = 0); grpmax FAF= 0.00075934.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00012416; MAF= 0.01242%, 31/249678 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000859107; MAF= 0.08591%, 20/23280 alleles, homozygotes = 0); grpmax FAF= 0.00052743.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0058%
· 90 / 1,549,338
0 hom · FAF 0.076%
0 hom · FAF 0.076%
African/African American 68 / 72,406 |
0.094% |
Admixed American 10 / 50,446 |
0.02% |
Remaining individuals 5 / 59,892 |
0.0083% |
South Asian 1 / 82,454 |
0.0012% |
European (non-Finnish) 6 / 1,142,370 |
0.00053% |
+ 5 not observed (European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.012%
· 31 / 249,678
0 hom · FAF 0.053%
0 hom · FAF 0.053%
African/African American 20 / 23,280 |
0.086% |
Admixed American 9 / 26,068 |
0.035% |
Remaining individuals 1 / 6,166 |
0.016% |
European (non-Finnish) 1 / 119,282 |
0.00084% |
+ 4 not observed (Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory) and as Benign (1 clinical laboratory) and as Likely benign by ClinGen Brain Malformations Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links