NM_000548.5:c.2356-15T>A

TSC2 · NP_000539.2:p.? · NM_000548.5

GRCh37: chr16:2124186 T>A · GRCh38: chr16:2074185 T>A

Gene: TSC2 Transcript: NM_000548.5

Final call

VUS

PM2_supporting BP4_supporting

Variant details

Gene

TSC2

Transcript

NM_000548.5

Protein

NP_000539.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

In silico splicing prediction is consistent with no significant splice effect, with SpliceAI maximal delta score 0.14.

Final determination: The observed evidence consists of one supporting pathogenic criterion and one supporting benign criterion, which does not satisfy any ACMG/AMP combination rule for likely pathogenic, pathogenic, likely benign, or benign; therefore the variant is classified as of uncertain significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	NM_000548.5:c.2356-15T>A is a noncanonical intronic variant at position -15, not a predicted null variant under generic ACMG PVS1. SpliceAI shows a low maximal delta score of 0.14, which does not support a loss-of-function splicing effect.	spliceai PMID:25741868
PS1	N/A	PS1 is a same-amino-acid criterion for protein-altering variants and is not applicable to this intronic variant with no established amino-acid change.	PMID:25741868
PS2	Not assessed	No confirmed de novo data with maternity and paternity confirmation were identified.
PS3	Not assessed	No well-established functional studies showing a damaging effect were identified.	PMID:25741868
PS4	Not assessed	No case-control enrichment or statistically increased prevalence in affected individuals was identified.	clinvar
PM1	Not met	No mutational hot spot or well-established critical functional domain evidence was identified for this intronic position.
PM2	Met	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 gnomad_v4
PM3	Not assessed	No recessive trans observations were identified.
PM4	N/A	PM4 addresses protein length changes and is not applicable to this intronic variant.	PMID:25741868
PM5	N/A	PM5 applies to a novel missense change at a residue with a different pathogenic missense change and is not applicable to this intronic variant.	PMID:25741868
PM6	Not assessed	No assumed de novo data without full parental confirmation were identified.
PP1	Not assessed	No segregation data were identified.
PP2	N/A	PP2 is a missense-specific criterion and is not applicable to this intronic variant.	PMID:25741868
PP3	Not met	Available computational splicing evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact, with maximal delta score 0.14.	spliceai
PP4	Not assessed	No phenotype-specific evidence for a highly specific TSC2-associated presentation was identified.
PP5	Not assessed	ClinVar contains mixed submitter classifications and no expert panel assertion. A qualifying pathogenic assertion from a reputable source without accessible primary data was not established.	clinvar
BA1	Not met	The allele frequency does not meet the benign stand-alone threshold used here. The highest robust frequencies in the reviewed gnomAD datasets are below 1%.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency does not exceed the benign strong threshold used here. The highest robust frequencies in the reviewed gnomAD datasets remain below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a way that satisfies BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies showing no damaging effect were identified.	PMID:25741868
BS4	Not assessed	No segregation evidence showing lack of segregation with disease was identified.
BP1	N/A	BP1 is a missense-specific criterion and is not applicable to this intronic variant.	PMID:25741868
BP2	Not assessed	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.
BP3	N/A	BP3 addresses in-frame indels in repetitive regions and is not applicable to this intronic single-nucleotide variant.	PMID:25741868
BP4	Met	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
BP5	Not assessed	No alternate molecular basis explaining disease while rendering this variant incidental was identified.
BP6	Not assessed	ClinVar shows mixed submitter classifications and no expert panel review. A qualifying benign assertion from a reputable source without accessible primary data was not established.	clinvar
BP7	Not assessed	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.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.