NM_000548.5:c.729C>G (p.Leu243=) is a synonymous variant in exon 8 of TSC2 with an overall allele frequency of 0.316-0.355% in gnomAD, exceeding the BS1 threshold of >0.3%.1 This variant has been observed in 10 homozygous individuals in gnomAD v4.1 among 1,612,278 alleles, constituting strong evidence for benignity in a dominant disorder (BS2).2 SpliceAI predicts no splice impact (max delta = 0.01), and the variant is synonymous with no predicted effect on protein sequence, supporting multiple benign computational evidence lines (BP4, BP7).3 ClinVar classifies this variant as Benign/Likely benign across 21 clinical laboratory submissions (15 Benign, 6 Likely benign), with criteria provided and no conflicting pathogenic interpretations (BP6).4 No pathogenic criteria are met. PVS1, PS1, and PM5 are not applicable to this synonymous variant. PS2, PS3, PS4, PS5, PM1, PM2, PM6, PP3, and PP5 are not met. PP1, PP4, BS4, BP2, and BP5 are not assessed due to absence of data. BA1 is not met (overall AF <1%). BP1 and PP2 are not applicable to synonymous variants.5 Applying generic ACMG/AMP 2015 final combination rules: two strong benign criteria (BS1, BS2) alone satisfy the classification threshold for Benign. Additionally, three supporting benign criteria (BP4, BP6, BP7) reinforce the benign classification.6
TSC2
Final classification
Benign
TSC2 c.729C>G · p.Leu243=
TSC2
NM_000548.5:c.729C>G (p.Leu243=) is a synonymous variant in exon 8 of TSC2 with an overall allele frequency of 0.316-0.355% in gnomAD, exceeding the BS1 threshold of >0.3%.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 strong benign, BS2 strong benign, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 2 strong benign + 3 supporting benign, which maps to Benign.
Classification rationale
BS1BS2BP4BP6BP7
Benign
TSC2 c.729C>G
BS1 + BS2 + BP4 + BP6 + BP7
→
Benign
5
pvs1_generic_framework ↗generic_acmg_combination_rules
6
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 · 5 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 · supports benign
gnomAD v4.1
gnomAD v2.1
Population frequency
10
homozygotes observed in gnomAD v4.1. Healthy biallelic carriers are difficult to reconcile with a fully penetrant loss-of-function disease allele.
Overall AF
5099 / 1,612,278
0.32%
Highest · European (Finnish)
1.2%
Homozygotes
10
grpmax FAF
0.3%
Allele frequency by ancestry — gnomAD v4.1
observed in 7 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (Finnish) | 753 / 62,138 | 1.2% | 4 |
| Ashkenazi Jewish | 119 / 29,606 | 0.4% | 0 |
| European (non-Finnish) | 3696 / 1,180,020 | 0.31% | 5 |
| South Asian | 210 / 91,084 | 0.23% | 0 |
| Admixed American | 94 / 60,024 | 0.16% | 1 |
| Middle Eastern | 3 / 6,062 | 0.049% | 0 |
| African/African American | 31 / 75,050 | 0.041% | 0 |
| Amish | 0 / 912 | — | — |
| East Asian | 0 / 44,890 | — | — |
“
This variant is present in gnomAD v4.1 (AF= 0.00316261; MAF= 0.31626%, 5099/1612278 alleles, homozygotes = 10) and has highest observed frequency in the European (Finnish) population (AF= 0.0121182; MAF= 1.21182%, 753/62138 alleles, homozygotes = 4); grpmax FAF= 0.00304706.
Overall AF
1000 / 281,464
0.36%
Highest · European (Finnish)
1.2%
Homozygotes
0
grpmax FAF
0.57%
Allele frequency by ancestry — gnomAD v2.1
observed in 7 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (Finnish) | 284 / 23,748 | 1.2% | 0 |
| Ashkenazi Jewish | 47 / 10,370 | 0.45% | 0 |
| Remaining individuals | 30 / 7,218 | 0.42% | 0 |
| European (non-Finnish) | 507 / 129,170 | 0.39% | 0 |
| South Asian | 57 / 30,616 | 0.19% | 0 |
| Admixed American | 59 / 35,438 | 0.17% | 0 |
| African/African American | 16 / 24,956 | 0.064% | 0 |
| East Asian | 0 / 19,948 | — | — |
“
This variant is present in gnomAD v2.1 (AF= 0.00355285; MAF= 0.35529%, 1000/281464 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.0119589; MAF= 1.19589%, 284/23748 alleles, homozygotes = 0); grpmax FAF= 0.0056912.
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Benign (15 clinical laboratories) and as Likely benign (6 clinical laboratories). (ClinVarID = 49382)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104587071, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · 13 PMIDs triaged · 8 high-priority
13papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
15798777 ↗
de novo
Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype--phenotype correlations and comparison of diagnostic DNA techniques in Tuberous Sclerosis Complex.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by the development of hamartomas in multiple organs and tissues. TSC is caused by mutations in either the TSC1 or TSC2 gene. We searched for mutations in both genes in a cohort of 490 patients diagnosed with or suspected of having TSC using a combination of denaturing gradient gel electrophoresis, single-strand confor
PM6PP5PS2PS4
24033266 ↗
functional
A systematic approach to assessing the clinical significance of genetic variants.
Molecular genetic testing informs diagnosis, prognosis, and risk assessment for patients and their family members. Recent advances in low-cost, high-throughput DNA sequencing and computing technologies have enabled the rapid expansion of genetic test content, resulting in dramatically increased numbers of DNA variants identified per test. To address this challenge, our laboratory has developed a s
BS3PP5PS3PS4
25741868 ↗
functional
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic
BS3PP5PS3PS4
9829910 ↗
splicing rna
Exon scanning of the entire TSC2 gene for germline mutations in 40 unrelated patients with tuberous sclerosis.
Tuberous sclerosis complex (TSC) is a dominantly inherited multisystem disorder resulting in the development of hamartomatous growths in many organs. Genetic heterogeneity has been demonstrated linking the familial cases to either TSC1 at 9q34.3, or TSC2 at 16p13.3. About two-thirds of the TSC cases are sporadic and appear to represent new mutations. While both genes are thought to account for all
BP7PP3PP5PS4PVS1
23519317 ↗
case observation
Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.
The autism spectrum disorders are a collective of conditions that have in common impaired socialization and communication in association with stereotypic behaviors. The reported incidence of autism spectrum disorders has increased dramatically over the past two decades. In addition, increased attention has been paid to these conditions by both lay and professional groups. These trends have resulte
PP5PS4
23788249 ↗
case observation
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the pati
PP5PS4
25356965 ↗
case observation
ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
These recommendations are designed primarily as an educational resource for medical geneticists and other health-care providers to help them provide quality medical genetics services. Adherence to these recommendations does not necessarily ensure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedure
PP5PS4
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PP5PS4
Sources & reference links