0%
TSC2c.29G>TUncertain significance
Print report
Variant interpretation report

TSC2 c.29G>T, p.(Gly10Val)

NM_000548.4:c.29G>T NP_000539.2:p.(Gly10Val) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About TSC2

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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%).

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

27 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 2

PM2 SupportingNM_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%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • Absent from gnomAD v4.1 (0 alleles)
  • Absent from gnomAD-Canada v1.0 (0 alleles)
Still missing
  • Larger population datasets may eventually detect this variant at very low frequency.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.254 (benign range
  • threshold >0.5 for pathogenic)
  • BayesDel score 0.012 (benign range
  • threshold >0.07 for damaging)
  • SpliceAI max delta 0.00 (no splicing alteration predicted)
Still missing
  • In silico predictions are supporting-level evidence only
  • confidence increases with experimental validation.
Sources
revelbayesdelspliceai ↗

Not met · 21 · evaluated, threshold not reached

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. No same-codon comparator variant with established pathogenicity was identified. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator at codon 10 identified.
Still missing
  • No same-codon pathogenic variants identified.
PS2 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. Details ▾Hide ▴
Evidence considered
  • No de novo report found in ClinVar
  • literature
  • or databases.
Still missing
  • No de novo testing data available.
PS3 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. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.254 (below pathogenic threshold of 0.5)
  • BayesDel score 0.012 (below damaging threshold of 0.07)
  • SpliceAI max delta 0.00 (no splicing impact)
  • OncoKB: Unknown Oncogenic Effect
  • COSMIC: absent
Still missing
  • No experimental functional studies for this variant or a systematically characterized range covering codon 10.
Sources
revelbayesdelspliceai ↗oncokb ↗
PS4 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. Details ▾Hide ▴
Evidence considered
  • ClinVar VCV000937943: single submitter (Labcorp/Invitae)
  • classified as Uncertain Significance.
Still missing
  • No case-control or prevalence data available.
Sources
clinvar ↗
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. 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. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: no significant hotspot at codon 10.
  • Variant at N-terminus
  • outside TSC2 GAP domain (aa 1517–1674) and other known functional domains.
PM6 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. Details ▾Hide ▴
Evidence considered
  • No de novo report in ClinVar or literature.
Still missing
  • No de novo testing data available.
PP1 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. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family studies available.
PP2 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. Details ▾Hide ▴
Evidence considered
  • HCI prior not available for TSC2 (gene not supported).
Still missing
  • No TSC2-specific missense constraint data.
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.254 (benign range)
  • BayesDel 0.012 (benign range)
  • SpliceAI 0.00 (no splicing impact)
Sources
revelbayesdelspliceai ↗
PP4 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. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data available.
Still missing
  • No phenotype information for individuals carrying this variant.
PP5 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. Details ▾Hide ▴
Evidence considered
  • ClinVar VCV000937943: Uncertain Significance
  • 1-star review status (criteria provided
  • single submitter)
  • Submitter: Labcorp Genetics (formerly Invitae)
  • No expert panel submission available
Still missing
  • No expert panel review of this variant.
Sources
clinvar ↗
BA1 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1. BA1 threshold (>1%) not met.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1. BS1 threshold (>0.3%) not met.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 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. Details ▾Hide ▴
Evidence considered
  • No healthy adult carrier data available.
Still missing
  • No healthy-control carrier frequency data.
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. In silico predictions (REVEL, BayesDel, SpliceAI) are assessed under BP4 rather than BS3, which requires experimental functional evidence. Details ▾Hide ▴
Evidence considered
  • No variant-specific experimental functional studies available.
Still missing
  • No functional studies testing this variant.
BS4 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. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family segregation data.
BP1 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. Details ▾Hide ▴
Evidence considered
  • TSC2 has both pathogenic missense and truncating variants
  • missense is a recognized disease mechanism.
BP2 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. Details ▾Hide ▴
Evidence considered
  • No trans-configuration data available.
Still missing
  • No data on variant in trans with 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. BP5 requires identification of an alternative pathogenic variant that explains the disease in a case where the variant of interest was also found. Details ▾Hide ▴
Evidence considered
  • No alternative molecular basis identified in the case.
Still missing
  • Information about alternative genetic findings not available.
BP6 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. Details ▾Hide ▴
Evidence considered
  • ClinVar VCV000937943: Uncertain Significance
  • 1-star (single submitter). Not classified as Benign or Likely Benign.
Sources
clinvar ↗
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. 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. Details ▾Hide ▴
Evidence considered
  • No evidence that other amino acid substitutions at codon 10 are benign.
Still missing
  • No benign variation data at codon 10.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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). Details ▾Hide ▴
Evidence considered
  • Variant is missense (p.Gly10Val)
  • classified as 'other' bucket by PVS1 variant assessment
  • apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessmentpvs1_gene_context
PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned 0 same-residue candidates. No pathogenic comparator at Gly10.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions with no known function. This variant is a single nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
TSC2
Transcript
NM_000548.4
Coding (HGVS c.)
NM_000548.4:c.29G>T
Protein (HGVS p.)
NP_000539.2:p.(Gly10Val)
GRCh38
chr16:2048644 G>T
GRCh37
chr16:2098645 G>T
ClinVar
937943

Gene diagram

Every interpreted variant in TSC2, mapped onto the exon structure of NM_000548.4. Select a row to find it on the plot.

TSC2NM_000548.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.010

Other predictors

REVEL
0.254
BayesDel
0.012

How the predictions were used

BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.254 (benign range
  • threshold >0.5 for pathogenic)
  • BayesDel score 0.012 (benign range
  • threshold >0.07 for damaging)
  • SpliceAI max delta 0.00 (no splicing alteration predicted)
Still missing
  • In silico predictions are supporting-level evidence only
  • confidence increases with experimental validation.
Sources
revelbayesdelspliceai ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.254 (benign range)
  • BayesDel 0.012 (benign range)
  • SpliceAI 0.00 (no splicing impact)
Sources
revelbayesdelspliceai ↗
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. 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. Details ▾Hide ▴
Evidence considered
  • No evidence that other amino acid substitutions at codon 10 are benign.
Still missing
  • No benign variation data at codon 10.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.254. BayesDel score = 0.0119073.

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Tuberous Sclerosis Complex.
    Adam MP et al. · 1993
    GeneReviews overview of Tuberous Sclerosis Complex covering TSC1 and TSC2 gene-level clinical features, diagnostic criteria, and management. NM_000548.4:c.29G>T was not identified in this review.
    Does not name this variant
    PMID 20301399 ↗
  • Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.
    Schaefer GB et al. · 2013
    ACMG practice guideline on clinical genetics evaluation for autism spectrum disorders, providing tiered diagnostic recommendations including chromosomal microarray, fragile X, MECP2, and PTEN testing. NM_000548.4:c.29G>T was not identified in this guideline.
    Does not name this variant
    PMID 23519317 ↗
  • ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
    Green RC et al. · 2013
    ACMG recommendations for reporting incidental findings in clinical exome and genome sequencing, establishing the initial 56-gene secondary findings list. NM_000548.4:c.29G>T was not identified in this policy statement.
    Does not name this variant
    PMID 23788249 ↗
  • ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
    ACMG Board of Directors · 2015
    Updated ACMG policy statement on secondary findings in clinical genome-scale sequencing, addressing opt-out provisions and informed consent. NM_000548.4:c.29G>T was not identified in this policy statement.
    Does not name this variant
    PMID 25356965 ↗
  • 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).
    Miller DT et al. · 2022
    ACMG SF v3.1 list of genes recommended for return as secondary findings from clinical exome and genome sequencing. TSC2 (OMIM 613254) is included for Tuberous Sclerosis Complex with recommendation to report all pathogenic and likely pathogenic variants. NM_000548.4:c.29G>T was not specifically mentioned.
    Does not name this variant
    PMID 35802134 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 1 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.