NM_000548.4:c.29G>T (p.Gly10Val) is a missense variant in exon 2 of TSC2, located at the N-terminus outside known functional domains. The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at supporting strength.1 Multiple in silico predictors (REVEL 0.254, BayesDel 0.012, SpliceAI 0.00) consistently predict a benign effect, meeting BP4 at supporting benign strength.2 ClinVar VCV000937943 classifies this variant as Uncertain Significance based on a single submitter. No variant-specific functional, segregation, de novo, or case-control evidence was identified in the literature.3 Six publications were reviewed, including ACMG secondary findings guidelines (PMID:23788249, PMID:25356965, PMID:35802134), autism diagnostic guidelines (PMID:23519317), GeneReviews TSC overview (PMID:20301399), and the Sherloc classification framework (PMID:28492532). None mention NM_000548.4:c.29G>T directly.4 The evidence profile is balanced with one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), consistent with a classification of Uncertain Significance.
TSC2
Final classification
VUS
TSC2 c.29G>T · p.Gly10Val
TSC2
NM_000548.4:c.29G>T (p.Gly10Val) is a missense variant in exon 2 of TSC2, located at the N-terminus outside known functional domains.
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 + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
TSC2 c.29G>T
PM2 + BP4
→
VUS
Gene diagram
· NM_000548.4 · variants mapped to exon structure
TSC2
NM_000548.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_000548.4:c.29G>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada. Under generic ACMG/AMP rules (non-VCEP), absence from population databases meets PM2 at supporting level (allele frequency <0.1%).
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. REVEL score is 0.254 (below 0.5 pathogenic threshold), BayesDel score is 0.012 (below 0.07 damaging threshold), and SpliceAI max delta score is 0.00 (no predicted splicing impact). Three independent in silico predictors consistently predict a benign effect.
REVEL score 0.254 (benign rangethreshold >0.5 for pathogenic)BayesDel score 0.012 (benign range
Assessed · not applied
Pathogenic
PS1
No alternative nucleotide change at NM_000548.4:c.29 resulting in the same amino acid substitution (p.Gly10) has been reported as pathogenic.
PS2
No de novo observation was identified for NM_000548.4:c.29G>T in any reviewed publication or database entry.
PS3
No functional studies have directly tested NM_000548.4:c.29G>T (p.Gly10Val) or a systematically characterized range that includes codon 10.
PS4
No case-control or enrichment data support an increased prevalence of NM_000548.4:c.29G>T in affected individuals versus controls.
PM1
p.Gly10Val is located at the extreme N-terminus of TSC2 (amino acid 10 of 1807), far outside the GAP catalytic domain (residues 1517–1674) and other characterized functional domains.
PM6
No de novo observation was identified for NM_000548.4:c.29G>T in any reviewed source.
PP1
No segregation data are available for NM_000548.4:c.29G>T.
PP2
HCI prior probability data are not available for TSC2 (gene not supported).
PP3
Multiple in silico tools consistently predict a benign effect for NM_000548.4:c.29G>T.
PP4
No patient-specific phenotypic data were available for review.
PP5
ClinVar VCV000937943 is classified as Uncertain Significance by a single clinical laboratory (Labcorp/Invitae) with review status 'criteria provided, single submitter' (1-star).
Benign
BA1
NM_000548.4:c.29G>T is absent from gnomAD v2.1 and v4.1.
BS1
NM_000548.4:c.29G>T is absent from gnomAD v2.1 and v4.1.
BS2
No data are available regarding observation of NM_000548.4:c.29G>T in healthy adult individuals.
BS3
No well-established in vitro or in vivo functional studies have directly tested NM_000548.4:c.29G>T and shown no damaging effect on protein function or splicing.
BS4
No segregation data are available for NM_000548.4:c.29G>T to demonstrate lack of co-segregation with disease.
BP1
BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease.
BP2
No data are available on observation of NM_000548.4:c.29G>T in trans with a known pathogenic variant.
BP5
No alternative molecular basis for disease was identified in the individual carrying NM_000548.4:c.29G>T that would explain the phenotype.
BP6
ClinVar VCV000937943 is classified as Uncertain Significance (not Benign or Likely Benign) with review status 'criteria provided, single submitter' (1-star).
BP7
BP7 applies to silent variants with no predicted splice impact, or missense variants at positions where an alternative amino acid change is established as benign.
N/A · 3
PVS1 · PM5 · BP3
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 = 937943)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.254. BayesDel score = 0.0119073.
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 · 5 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
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