Classification rationale

BS1BP4 Likely Benign

TSC2 c.3884-17C>G

The TSC2 NM_000548.5:c.3884-17C>G (NP_000539.2:p.?) variant has been reported in ClinVar predominantly as benign or likely benign, without an expert panel review.¹ This variant is present in population databases, including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, with the highest observed frequency of 0.65789% (6/912) in the Amish population in gnomAD v4.1, which is above the default BS1 threshold of 0.3% and below the default BA1 threshold of 1%.² In silico splicing analysis does not support a deleterious effect, as SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.³

BS1 + BP4 → Likely Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 spliceai ↗

Gene diagram · NM_000548.5 · variants mapped to exon structure

TSC2 NM_000548.5

Fetching transcript structure from UCSC…

Applied criteria · 2 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

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000896273; MAF= 0.08963%, 1407/1569834 alleles, homozygotes = 0) and has highest observed frequency in the Amish population (AF= 0.00657895; MAF= 0.65789%, 6/912 alleles, homozygotes = 0); grpmax FAF= 0.00109091.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00061533; MAF= 0.06153%, 131/212894 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00125942; MAF= 0.12594%, 115/91312 alleles, homozygotes = 0); grpmax FAF= 0.00162279.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.000434499; MAF= 0.04345%, 8/18412 alleles, homozygotes = 0) and has highest observed frequency in the amr population (AF= 0.00119332; grpmax FAF95= 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.09% · 1407 / 1,569,834
0 hom · FAF 0.11%

Amish 6 / 912	0.66%
European (non-Finnish) 1323 / 1,157,912	0.11%
Remaining individuals 34 / 60,900	0.056%
Admixed American 22 / 52,862	0.042%
European (Finnish) 17 / 59,594	0.029%
African/African American 5 / 74,388	0.0067%

+ 4 not observed (East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.062% · 131 / 212,894
0 hom · FAF 0.16%

European (non-Finnish) 115 / 91,312	0.13%
European (Finnish) 7 / 19,712	0.036%
Admixed American 8 / 27,468	0.029%
Remaining individuals 1 / 5,910	0.017%

+ 4 not observed (African/African American, Ashkenazi Jewish, East Asian, South Asian)

gnomAD Canada 🇨🇦

0.043% · 8 / 18,412
0 hom

indel · split

Latino/Admixed American 1 / 838	0.12%
European (non-Finnish) 7 / 11,736	0.06%

+ 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 49513)

ClinVar ↗

In silico

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

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV104375921, n = 2 times).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 9 PMIDs not cited in assessment

25741868 ↗ 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. CLINVAR

31275557 ↗ Pan-cancer repository of validated natural and cryptic mRNA splicing mutations. CLINVAR

20301399 ↗ Tuberous Sclerosis Complex. CLINVAR

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

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. 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

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR