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 applied · 16 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

BS1 strong Benign

Population frequency is above the default BS1 threshold of 0.3%. In gnomAD v4.1, this variant has an Amish population frequency of 0.65789% (6/912), which exceeds 0.3%, and the variant is also recurrent across gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada.

gnomAD v4.1 Amish AF 0.00657895 (6/912).gnomAD v2.1 total AF 0.00061533 (131/212894).gnomAD-Canada total AF 0.000434499 (8/18412).

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Available computational evidence supports no meaningful splice effect. SpliceAI predicts no significant splice impact with a max delta score of 0.00, which argues against an abnormal splicing consequence for this intronic change.

SpliceAI max delta score 0.00.

spliceai ↗

Assessed · not applied

Pathogenic

PVS1 TSC2 loss of function is an established disease mechanism, but this intronic variant is at c.3884-17 and is not a canonical +/-1,2 splice-site variant, nonsense variant, or frameshift variant.

PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant.

PS3 No well-established functional study was identified showing that this variant damages TSC2 function or causes abnormal splicing.

PS4 No case-control enrichment data or counted series of affected individuals sufficient for PS4 were identified for this variant.

PM2 Population frequency is not low enough for PM2.

PM6 No presumed de novo report with incomplete parental confirmation was identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 Available computational evidence does not support a damaging effect on splicing.

PP4 No phenotype-specific evidence was provided to show a highly specific TSC2-related clinical presentation attributable to this variant.

Benign

BA1 Population frequency does not reach the default BA1 threshold of 1%.

BS2 No data were identified showing this variant in definitively unaffected individuals at an evidence level sufficient for BS2.

BS3 No well-established functional study was identified showing normal splicing or preserved TSC2 function for this variant.

BS4 No non-segregation data were identified for this variant.

BP2 No confirmed co-occurrence with another pathogenic variant in a phase context informative for BP2 was identified.

BP5 No alternate molecular explanation for phenotype was provided that would support BP5.

BP7 This intronic variant is outside the canonical splice consensus and SpliceAI predicts no significant splice impact, but no direct RNA evidence was identified and the available evidence was not sufficient to apply BP7 confidently in this review.

N/A · 10 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP5 · BP1 · BP3 · BP6

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

Re-run this variant?