NM_002524.4:c.291-8G>A is an intronic variant in NRAS (intron 2, c.291-8).

The ClinGen RASopathy Expert Panel VCEP v2.3.0 was applied as the primary classification framework.

No pathogenic criteria were met. PVS1, PS1, PS5, PM1, PM5, PP2, PP4, PP5, BS3, BP1, BP3, BP6, PM3, and PM4 are not applicable to this intronic variant per VCEP specifications.

Two benign supporting criteria are met: BP4 (SpliceAI predicts no splicing impact; max delta 0.01; predicted outcome does not match gain-of-function disease mechanism) and BP7 (intronic variant at non-canonical position with no predicted splice effect).

The variant is present in gnomAD at low frequency: v2.1 AF=0.0064% (18/282,784 alleles), v4.1 AF=0.010% (167/1,607,416 alleles, 1 homozygote). These frequencies do not reach VCEP thresholds for BA1 (>=0.05%) or BS1 (>=0.025%), but the presence in population databases precludes PM2 (which requires absence from gnomAD).

No de novo occurrences, functional studies, cosegregation data, or case-control enrichment have been reported for this variant in ClinVar or the published literature.

Per VCEP Rule 19, >=2 supporting benign criteria (BP4 + BP7) classifies this variant as Likely Benign.

This classification is concordant with the ClinGen RASopathy VCEP expert panel assessment of Likely Benign (ClinVar Variation ID 44575).