NM_000548.5:c.97G>C (p.Gly33Arg) in TSC2 is a missense variant absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, supporting PM2 at supporting strength.1 Multiple lines of computational evidence (REVEL 0.212, BayesDel 0.118, SpliceAI max delta 0.00) suggest no deleterious impact on the gene product, supporting BP4 at supporting benign strength.2 No functional studies, case reports, segregation data, de novo observations, or ClinVar pathogenic classifications exist for this specific variant. The sole ClinVar submission classifies it as Uncertain Significance.3 Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) yields a final classification of Variant of Uncertain Significance (VUS).4
TSC2
Final classification
VUS
TSC2 c.97G>C · p.Gly33Arg
TSC2
NM_000548.5:c.97G>C (p.Gly33Arg) in TSC2 is a missense variant absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, supporting PM2 at supporting strength.
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, BP4 supporting benign; combination = 1 supporting, which maps to VUS because the evidence is conflicting.
Classification rationale
PM2
BP4
VUS
TSC2 c.97G>C
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_000548.5 · variants mapped to exon structure
TSC2
NM_000548.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_000548.5:c.97G>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). For non-VCEP assessment under generic ACMG/AMP, PM2 is applied when allele frequency is below 0.1% in all population databases. Complete absence across all queried populations supports PM2 at supporting strength.
Absent from gnomAD v2.1 (0 alleles)gnomAD v4.1 (0 alleles)gnomAD-Canada v1.0 (0 alleles).
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.212 (below 0.5 pathogenic threshold). BayesDel score is 0.118 (low). SpliceAI predicts no splicing alteration (max delta score = 0.00). All three in silico predictors are concordant in not supporting a deleterious effect.
REVEL: 0.212. BayesDel: 0.118. SpliceAI: max delta 0.00. All predictors concordant for no damaging effect.
Assessed · not applied
Pathogenic
PS1
No evidence was identified that the same amino acid change (p.Gly33Arg) has been established as pathogenic via a different nucleotide change.
PS2
No de novo occurrence of NM_000548.5:c.97G>C has been reported.
PS3
No well-established in vitro or in vivo functional studies have tested NM_000548.5:c.97G>C (p.Gly33Arg).
PS4
No case-control or cohort study has demonstrated statistically significant enrichment of NM_000548.5:c.97G>C in affected individuals versus controls.
PM1
Residue Gly33 is located in exon 2, in the N-terminal region of TSC2, distant from the critical GAP domain (residues ~1517-1766).
PM6
No de novo observation of NM_000548.5:c.97G>C has been reported, with or without confirmation of paternity/maternity.
PP1
No segregation data are available for NM_000548.5:c.97G>C.
PP2
PP2 applies when a missense variant occurs in a gene with a low rate of benign missense variation and where missense is a common disease mechanism.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No specific phenotypic data or clinical information about the proband are available.
PP5
PP5 requires a reputable source (e.g., clinical diagnostic laboratory with expertise) to have classified the variant as pathogenic.
Benign
BA1
BA1 requires allele frequency above 1% in population databases.
BS1
BS1 requires allele frequency above 0.3% in population databases.
BS2
No observations of NM_000548.5:c.97G>C in healthy adults have been reported.
BS3
No well-established in vitro or in vivo functional studies demonstrate that NM_000548.5:c.97G>C has no damaging effect on protein function or splicing.
BS4
No evidence of non-segregation with disease in affected families has been reported.
BP1
BP1 applies when a missense variant occurs in a gene where truncating variants are the primary/only known disease mechanism.
BP2
No evidence that NM_000548.5:c.97G>C has been observed in trans with a known pathogenic TSC2 variant, or in cis with a pathogenic variant in this autosomal dominant disorder.
BP5
BP5 requires a reputable source to have classified the variant as benign or to report it as found in a case with an alternate molecular basis for disease.
BP6
No reputable source (e.g., ClinGen Expert Panel, professional society guideline) has classified NM_000548.5:c.97G>C as benign.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · 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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4802827)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.212. BayesDel score = 0.118026.
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. TSC2, a GTPase-activating protein, is altered by mutation in various cancers, including endometrial and colorectal cancer.
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
Triaged references · 8 PMIDs not cited in assessment
23519317 ↗
Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.
CLINVAR
23788249 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
CLINVAR
25356965 ↗
ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
CLINVAR
27854360 ↗
Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
CLINVAR
34012068 ↗
ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG).
CLINVAR
35802134 ↗
ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG).
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR