NM_001042749.1:c.482T>A (p.Leu161His) in STAG2 is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at moderate strength, though X-chromosome coverage caveats apply.1 SpliceAI predicts no splice impact (max delta 0.01) and BayesDel score is 0.0859 (low/benign range), meeting BP4 at supporting benign strength.2 This variant is absent from ClinVar and COSMIC and has not been reported in the literature; no functional, segregation, or case-control data are available for variant-specific assessment.3 With 1 moderate pathogenic criterion (PM2) and 1 supporting benign criterion (BP4), this variant does not meet the threshold for Likely Pathogenic or Likely Benign under generic ACMG/AMP 2015 combination rules (PMID:25741868). The variant is classified as a Variant of Uncertain Significance (VUS).4
STAG2
Final classification
VUS
STAG2 c.482T>A · p.Leu161His
STAG2
NM_001042749.1:c.482T>A (p.Leu161His) in STAG2 is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at moderate strength, though X-chromosome coverage caveats apply.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
STAG2 c.482T>A
PM2 + BP4
→
VUS
2
spliceai ↗bayesdel
4
generic_acmg_combination_rules
Gene diagram
· NM_001042749.1 · variants mapped to exon structure
STAG2
NM_001042749.1
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 22 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
review
Pathogenic
Absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0, meeting the PM2 threshold of <0.1% allele frequency in large population databases. Note: STAG2 is located on the X chromosome; absence from gnomAD should be interpreted with awareness of potentially reduced X-chromosome coverage in some regions.
Absent from gnomAD v2.1 (0 alleles).Absent from gnomAD v4.1 (0 alleles).Absent from gnomAD-Canada v1.0 (0 alleles).
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product or splicing. SpliceAI predicts no significant splice impact (max delta score 0.01), and BayesDel score is 0.086 (low, consistent with a benign effect on protein function). Two independent in silico tools support a neutral or benign interpretation.
SpliceAI max delta 0.01: no splice alteration predicted.BayesDel 0.0858646: score in the low/benign range.
Assessed · not applied
Pathogenic
PVS1
PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, or exon-level deletions) under the ClinGen SVI framework (PMC6185798).
PS1
Requires the same amino acid change (p.Leu161His) to have been previously established as pathogenic.
PS2
Requires a confirmed de novo observation with both maternity and paternity confirmed.
PS3
Requires well-established in vitro or in vivo functional studies demonstrating a damaging effect.
PS4
Requires a statistically higher prevalence of the variant in affected individuals versus controls.
PM1
Requires the variant to lie in a mutational hotspot or a well-characterized critical functional domain without benign variation.
PM5
Requires a different pathogenic missense change at the same residue (Leu161).
PM6
Requires a de novo observation without confirmation of paternity and maternity.
PP1
Requires cosegregation of the variant with disease in multiple affected family members.
PP2
Requires evidence that STAG2 has a low rate of benign missense variation and that missense variants are a common mechanism of disease.
PP3
Requires multiple lines of computational evidence to support a deleterious effect on the gene product.
PP4
Requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5
Requires a reputable source (e.g., ClinVar expert panel, clinical diagnostic laboratory) to have recently reported the variant as pathogenic.
Benign
BA1
Requires an allele frequency >1% in population databases (non-VCEP rule).
BS1
Requires an allele frequency >0.3% in population databases (non-VCEP rule).
BS2
Requires observation of the variant in a healthy adult individual for a disorder with full penetrance expected at an early age.
BS3
Requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing.
BS4
Requires lack of segregation with disease in affected family members.
BP1
Requires the variant to be a missense change in a gene for which primarily truncating variants cause disease.
BP2
Requires observation of the variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a known pathogenic variant.
BP5
Requires the variant to be found in a case with an alternate molecular basis for disease.
BP6
Requires a reputable source to have recently reported the variant as benign.
N/A · 4
PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
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 = 0.01). BayesDel score = 0.0858646.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. STAG2, a component of the cohesin complex, is recurrently altered by mutation in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links