Classification rationale

PM2 BP4 VUS

TSC2 c.2356-15T>A

The TSC2 c.2356-15T>A (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where aggregate submissions include Benign, Likely benign, and Uncertain significance classifications.¹ The variant is present at low frequency in population databases, with gnomAD v2.1 total AF 0.01435% (40/278790 alleles) and gnomAD v4.1 total AF 0.00571% (92/1610442 alleles), with no homozygotes reported.² In silico splicing prediction is consistent with no significant splice effect, with SpliceAI maximal delta score 0.14.³

PM2 + BP4 → VUS

1 cosmicclinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

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.

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

TSC2 NM_000548.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 20 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

The variant is rare in population databases by the default non-VCEP rarity threshold used here. In gnomAD v2.1 the total AF is 0.01435% (40/278790; no homozygotes) with highest observed AMR AF 0.09323%, and in gnomAD v4.1 the total AF is 0.00571% (92/1610442; no homozygotes) with grpmax FAF 0.00070689.

gnomAD v2.1 total AF 0.000143477; AMR AF 0.000932256; 0 homozygotesgnomAD v4.1 total AF 0.0000571272; grpmax FAF 0.00070689; 0 homozygotes

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting review Benign

Multiple computational splicing predictors support no significant impact on splicing. SpliceAI shows a maximal delta score of 0.14, and Pangolin scores are low.

SpliceAI max delta score 0.14Pangolin SG 0.02 and SL -0.03

spliceai ↗

Assessed · not applied · 5 not met · 15 not assessed

Pathogenic

PVS1 NM_000548.5:c.2356-15T>A is a noncanonical intronic variant at position -15, not a predicted null variant under generic ACMG PVS1.

PS2 No confirmed de novo data with maternity and paternity confirmation were identified.

PS3 No well-established functional studies showing a damaging effect were identified.

PS4 No case-control enrichment or statistically increased prevalence in affected individuals was identified.

PM1 No mutational hot spot or well-established critical functional domain evidence was identified for this intronic position.

PM3 No recessive trans observations were identified.

PM6 No assumed de novo data without full parental confirmation were identified.

PP1 No segregation data were identified.

PP3 Available computational splicing evidence does not support a deleterious effect.

PP4 No phenotype-specific evidence for a highly specific TSC2-associated presentation was identified.

PP5 ClinVar contains mixed submitter classifications and no expert panel assertion.

Benign

BA1 The allele frequency does not meet the benign stand-alone threshold used here.

BS1 The allele frequency does not exceed the benign strong threshold used here.

BS2 No evidence was identified showing this variant in healthy adult individuals in a way that satisfies BS2.

BS3 No well-established functional studies showing no damaging effect were identified.

BS4 No segregation evidence showing lack of segregation with disease was identified.

BP2 No phase data demonstrating the variant in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant, were identified.

BP5 No alternate molecular basis explaining disease while rendering this variant incidental was identified.

BP6 ClinVar shows mixed submitter classifications and no expert panel review.

BP7 The variant is noncanonical intronic and computational splicing evidence argues against splice disruption, but the reviewed materials did not provide additional evidence needed to support BP7 confidently under a strict generic ACMG approach.

N/A · 6 PS1 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.71272e-05; MAF= 0.00571%, 92/1610442 alleles, homozygotes = 0) and has highest observed frequency in the HGDP:BASQUE population (AF= 0.0227273; MAF= 2.27273%, 1/44 alleles, homozygotes = 0); grpmax FAF= 0.00070689.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000143477; MAF= 0.01435%, 40/278790 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000932256; MAF= 0.09323%, 33/35398 alleles, homozygotes = 0); grpmax FAF= 0.00067374.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0057% · 92 / 1,610,442
0 hom · FAF 0.071%

HGDP:BASQUE 1 / 44	2.3%
1KG:CLM 1 / 188	0.53%
Admixed American 57 / 60,016	0.095%
HGDP:XY 1 / 1,122	0.089%
1KG:XX 1 / 2,476	0.04%
Remaining individuals 6 / 62,308	0.0096%
African/African American 3 / 74,996	0.004%
European (non-Finnish) 26 / 1,179,812	0.0022%

+ 86 not observed (European (Finnish), Middle Eastern, South Asian, Ashkenazi Jewish, East Asian, Amish, HGDP:JAPANESE, HGDP:ADYGEI, HGDP:ORCADIAN, HGDP:BANTUSOUTHAFRICA, HGDP:YAKUT, HGDP:HAN, HGDP:UYGUR, HGDP:BALOCHI, HGDP:BEDOUIN, HGDP:RUSSIAN, HGDP:DAUR, HGDP:PIMA, HGDP:HEZHEN, HGDP:BIAKA, HGDP:MIAO, HGDP:SINDHI, HGDP:NORTHERNHAN, HGDP:OROQEN, HGDP:SAN, HGDP:TU, HGDP:TUSCAN, HGDP:MBUTI, HGDP:PALESTINIAN, HGDP:TUJIA, HGDP:DRUZE, HGDP:PATHAN, HGDP:MAKRANI, HGDP:BURUSHO, HGDP:MONGOLIAN, HGDP:BOUGAINVILLE, HGDP:PAPUANSEPIK, HGDP:YI, HGDP:NAXI, HGDP:LAHU, HGDP:SARDINIAN, HGDP:KARITIANA, HGDP:MOZABITE, HGDP:YORUBA, HGDP:DAI, HGDP:BERGAMOITALIAN, HGDP:CAMBODIAN, HGDP:FRENCH, HGDP:MANDENKA, HGDP:SURUI, HGDP:BRAHUI, HGDP:HAZARA, HGDP:KALASH, HGDP:PAPUANHIGHLANDS, HGDP:XIBO, HGDP:COLOMBIAN, HGDP:BANTUKENYA, HGDP:SHE, HGDP:MAYA, HGDP:XX, 1KG:ESN, 1KG:PUR, 1KG:PJL, 1KG:JPT, 1KG:CHB, 1KG:STU, 1KG:ITU, 1KG:TSI, 1KG:MXL, 1KG:CEU, 1KG:MSL, 1KG:BEB, 1KG:YRI, 1KG:FIN, 1KG:KHV, 1KG:CDX, 1KG:LWK, 1KG:ACB, 1KG:ASW, 1KG:IBS, 1KG:GBR, 1KG:PEL, 1KG:GIH, 1KG:CHS, 1KG:GWD, 1KG:XY)

gnomAD v2.1

0.014% · 40 / 278,790
0 hom · FAF 0.067%

Admixed American 33 / 35,398	0.093%
Remaining individuals 3 / 7,172	0.042%
European (non-Finnish) 4 / 126,084	0.0032%

+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (5 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14).

SpliceAI ↗

Functional No data

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

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

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

Hotspots

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

Sources & reference links

5Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

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