NM_002067.5:c.506_507delinsTT (p.Thr169Ile) in GNA11 is absent from all queried population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2_Supporting.1 The variant is not a null variant (nonsense, frameshift, or canonical splice site) and does not qualify for PVS1 per ClinGen SVI PVS1 recommendations (PMC6185798); it is an in-frame delins producing a single missense substitution.2 No additional pathogenic or benign criteria are met. Computational evidence (SpliceAI max delta = 0.02) does not support PP3 or BP4, and no functional, segregation, or case-level data are available. The variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 rules; PM2_Supporting alone is insufficient to reach Likely Pathogenic or Likely Benign.3
GNA11
Final classification
VUS
GNA11 c.506_507delinsTT · p.Thr169Ile
GNA11
NM_002067.5:c.506_507delinsTT (p.Thr169Ile) in GNA11 is absent from all queried population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2_Supporting.
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 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
GNA11 c.506_507delinsTT
PM2
→
VUS
2
pvs1_generic_framework ↗pvs1_variant_assessment
3
spliceai ↗generic_acmg_combination_rules
Gene diagram
· NM_002067.5 · variants mapped to exon structure
GNA11
NM_002067.5
Fetching transcript structure from UCSC…
Applied criteria · 1 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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 = 0.02).
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. GNA11, a G protein subunit, is recurrently mutated in uveal melanoma.
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