NM_000548.4:c.29G>T

TSC2 · NP_000539.2:p.(Gly10Val) · NM_000548.4

GRCh37: chr16:2098645 G>T · GRCh38: chr16:2048644 G>T

Gene: TSC2 Transcript: NM_000548.4

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

TSC2

Transcript

NM_000548.4

Protein

NP_000539.2:p.(Gly10Val)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Multiple in silico predictors (REVEL 0.254, BayesDel 0.012, SpliceAI 0.00) consistently predict a benign effect, meeting BP4 at supporting benign strength.

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.

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.

The evidence profile is balanced with one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), consistent with a classification of Uncertain Significance.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_000548.4:c.29G>T is a missense variant (p.Gly10Val). It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense substitutions under the ClinGen SVI framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No alternative nucleotide change at NM_000548.4:c.29 resulting in the same amino acid substitution (p.Gly10) has been reported as pathogenic. No same-codon comparator variant with established pathogenicity was identified.
PS2	Not met	No de novo observation was identified for NM_000548.4:c.29G>T in any reviewed publication or database entry. No parent-of-origin testing results are available.
PS3	Not met	No functional studies have directly tested NM_000548.4:c.29G>T (p.Gly10Val) or a systematically characterized range that includes codon 10. In silico predictors (REVEL 0.254, BayesDel 0.012, SpliceAI 0.00) all suggest a benign effect, consistent with absence of functional evidence for pathogenicity. OncoKB reports Unknown Oncogenic Effect. No COSMIC entries.	revel bayesdel spliceai oncokb
PS4	Not met	No case-control or enrichment data support an increased prevalence of NM_000548.4:c.29G>T in affected individuals versus controls. The variant has been reported in ClinVar as a VUS by a single clinical laboratory submitter, which does not constitute a statistically significant case series.	clinvar
PS5	N/A	PS5 is not applicable under generic ACMG/AMP 2015 framework. This criterion is a placeholder for recessive-disorder trans configurations and is not assessed for autosomal dominant TSC2.
PM1	Not met	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. No statistically significant mutational hotspot exists at this position (cancerhotspots.org negative). The variant does not lie within a well-characterized critical functional domain without benign variation.
PM2	Met	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%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants at codon 10 with established pathogenic classification were identified in ClinVar. PM5 candidate harvesting returned zero candidates. PM5 not applicable without a comparator.	pm5_candidates
PM6	Not met	No de novo observation was identified for NM_000548.4:c.29G>T in any reviewed source. No parent-of-origin testing results are available to confirm de novo status.
PP1	Not met	No segregation data are available for NM_000548.4:c.29G>T. No family studies or co-segregation analysis was identified in any reviewed publication or ClinVar submission.
PP2	Not met	HCI prior probability data are not available for TSC2 (gene not supported). No statistically significant missense constraint metric is available to support that missense variants are a common disease mechanism despite low benign missense variation in the gene.
PP3	Not met	Multiple in silico tools consistently predict a benign effect for NM_000548.4:c.29G>T. REVEL score 0.254 (below 0.5 pathogenic threshold), BayesDel score 0.012 (below 0.07 damaging threshold), and SpliceAI max delta score 0.00 (no splicing impact). The computational evidence does not support a damaging effect.	revel bayesdel spliceai
PP4	Not met	No patient-specific phenotypic data were available for review. The ClinVar submission (single submitter, VUS) does not include detailed phenotype information. PP4 requires that the variant be observed in a patient with a phenotype highly specific for the gene/disease.
PP5	Not met	ClinVar VCV000937943 is classified as Uncertain Significance by a single clinical laboratory (Labcorp/Invitae) with review status 'criteria provided, single submitter' (1-star). The classification is not Pathogenic or Likely Pathogenic. Under global PP5 rules, ClinVar 3-star expert panel classification is required for PP5 at supporting strength; this entry does not meet the star-rating threshold.	clinvar
BA1	Not met	NM_000548.4:c.29G>T is absent from gnomAD v2.1 and v4.1. BA1 requires an allele frequency >1% in population databases. The observed absence does not meet this threshold.	gnomad_v2 gnomad_v4
BS1	Not met	NM_000548.4:c.29G>T is absent from gnomAD v2.1 and v4.1. Under generic ACMG/AMP rules (non-VCEP), BS1 requires an allele frequency >0.3%. The observed absence does not meet this threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding observation of NM_000548.4:c.29G>T in healthy adult individuals. BS2 requires observation in a healthy adult for a fully penetrant disorder, or absence of phenotype is documented.
BS3	Not met	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. In silico predictions (REVEL, BayesDel, SpliceAI) are assessed under BP4 rather than BS3, which requires experimental functional evidence.
BS4	Not met	No segregation data are available for NM_000548.4:c.29G>T to demonstrate lack of co-segregation with disease. BS4 requires evidence that the variant does not segregate with disease in affected family members.
BP1	Not met	BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. While TSC2 haploinsufficiency through truncating variants is a well-established mechanism, pathogenic missense variants are also a known disease mechanism in TSC2 (particularly within the GAP domain and other regions). The gene does not meet the criterion that 'primarily' truncating variants cause disease.
BP2	Not met	No data are available on observation of NM_000548.4:c.29G>T in trans with a known pathogenic variant. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions with no known function. This variant is a single nucleotide substitution.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No alternative molecular basis for disease was identified in the individual carrying NM_000548.4:c.29G>T that would explain the phenotype. BP5 requires identification of an alternative pathogenic variant that explains the disease in a case where the variant of interest was also found.
BP6	Not met	ClinVar VCV000937943 is classified as Uncertain Significance (not Benign or Likely Benign) with review status 'criteria provided, single submitter' (1-star). BP6 requires classification as Benign or Likely Benign by a reputable source; under global BP6 rules, ClinVar 3-star expert panel classification is required at supporting strength. This entry meets neither threshold.	clinvar
BP7	Not met	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. NM_000548.4:c.29G>T is a missense substitution (p.Gly10Val). No evidence exists that other amino acid changes at codon 10 are tolerated; position 10 has not been established as a site of benign variation.

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