NM_006218.2:c.2015+9A>G

PIK3CA · NP_006209.2:p.? · NM_006218.2

GRCh37: chr3:178937849 A>G · GRCh38: chr3:179220061 A>G

Gene: PIK3CA Transcript: NM_006218.2

Final call

Likely Benign

BS1 strong BP6 supporting benign

Variant details

Gene

PIK3CA

Transcript

NM_006218.2

Protein

NP_006209.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

No variant-specific functional study was identified showing either an abnormal or a normal effect on PIK3CA splicing or function.

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.

Final determination: Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework yields a total score of -4, which maps to Likely Benign under the specified Tavtigian-style ranges.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PS1	N/A	This is an intronic c.2015+9A>G variant and does not create the same amino acid change as an established pathogenic missense variant, so PS1 is not applicable.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS2	Not assessed	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.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS3	Not assessed	No published RNA study, minigene assay, or other well-established functional assay was identified for this exact intronic variant, so PS3 cannot be applied.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS4	Not met	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. PS4 is therefore not met.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4 clinvar
PM1	Not met	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.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2	Not met	The Brain Malformations VCEP allows PM2 only for variants absent or extremely rare in controls, with one person maximum. This variant is present in gnomAD v2.1 at 31/249678 alleles (AF 0.01242%) and in gnomAD v4.1 at AF 0.00581%, with the highest observed African/African American frequency 0.09391%, so PM2 is not met.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable because this VCEP addresses disorders caused by heterozygous de novo or mosaic PIK3CA variants rather than a recessive biallelic mechanism.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM4	N/A	PM4 is not applicable under this VCEP framework.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM5	N/A	This is not a missense change at an amino acid residue, so PM5 is not applicable.	cspec
PM6	N/A	PM6 is not applicable under this VCEP framework.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP1	N/A	PP1 is not applicable because the relevant PIK3CA disease mechanism in this framework is typically de novo or mosaic rather than familial segregation.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP2	N/A	PP2 is a missense-specific rule based on missense constraint, and this variant is intronic, so PP2 is not applicable.	cspec
PP3	N/A	PP3 is not applicable in this Brain Malformations VCEP because PIK3CA disease is driven by gain-of-function variants and the specification does not use traditional computational pathogenicity prediction for this purpose.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP4	N/A	PP4 is not applicable in this framework because phenotype specificity is accounted for under PS4.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP5	N/A	PP5 is not used by this VCEP.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BA1	Not met	The BA1 threshold in this VCEP is >0.0926%. Although the highest observed African/African American frequency in gnomAD v4.1 is 0.09391%, the joint grpmax filtering allele frequency is 0.07593%, below the BA1 threshold, so BA1 was not applied from the available population evidence.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v4
BS1	Met	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.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires at least 3 homozygotes in gnomAD or at least 3 well-phenotyped unaffected family members. No homozygotes were observed in gnomAD v2.1 or v4.1, and no unaffected family data were identified, so BS2 is not met.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established study was identified showing that this variant has no effect on splicing or downstream PIK3CA function, so BS3 cannot be applied.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BS4	N/A	BS4 is not applicable in this framework.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1	N/A	BP1 is not applicable because loss of function is not the relevant disease mechanism in this PIK3CA framework.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not assessed	No phase data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 cannot be assessed.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3	N/A	BP3 is not applicable under this VCEP framework.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP4	Not assessed	BP4 for this VCEP requires at least 2 of 3 splicing tools to predict no splicing impact for an intronic non-canonical variant. A SpliceAI source was available, but no independently retrievable SpliceAI, varSEAK, and MaxEntScan result set was available to confirm a 2-of-3 benign splicing pattern, so BP4 could not be assessed.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 spliceai
BP5	Not assessed	No alternate molecular diagnosis was identified that would explain the phenotype independently of this variant, so BP5 cannot be assessed.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP6	Met	Expert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Likely benign.	cspec clinvar
BP7	Not assessed	BP7 for this VCEP requires a non-canonical intronic variant at a non-conserved nucleotide with PhyloP <0.1. No PhyloP conservation value was available to confirm this threshold, so BP7 could not be assessed.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PVS1	N/A	PVS1 is not applicable in the Brain Malformations PIK3CA framework because the disease mechanism is gain of function rather than loss of function, and this variant is also outside the canonical ±1,2 splice positions.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 pvs1_variant_assessment

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