Variant classification summary

NM_000548.5:c.3884-17C>G

TSC2 · NP_000539.2:p.? · NM_000548.5

GRCh37: chr16:2133679 C>G · GRCh38: chr16:2083678 C>G

Gene: TSC2 Transcript: NM_000548.5

Final call

Likely Benign

BS1 strong benign BP4 supporting benign

Variant details

Gene

TSC2

Transcript

NM_000548.5

Protein

NP_000539.2:p.?

gnomAD AF

0.0008962731091312839 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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%.

3

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	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. The generic PVS1 assessment does not place it in a default null-variant category, and no RNA evidence was identified to show a loss-of-function splicing effect.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework spliceai
PS1	N/A	This is an intronic variant with no established protein change, so same-amino-acid substitution logic does not apply.
PS2	Not assessed	No confirmed de novo occurrence with parental confirmation was identified for this variant.	clinvar
PS3	Not assessed	No well-established functional study was identified showing that this variant damages TSC2 function or causes abnormal splicing.	clinvar spliceai
PS4	Not assessed	No case-control enrichment data or counted series of affected individuals sufficient for PS4 were identified for this variant.	clinvar
PM1	N/A	This intronic variant is not located in a defined mutational hot spot or critical functional protein domain used for PM1.
PM2	Not met	Population frequency is not low enough for PM2. In gnomAD v2.1, this variant is present at 0.12594% in the European non-Finnish population, which is above the default PM2 rarity threshold of 0.1%, and it is also present in gnomAD v4.1 and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	TSC2-related disease is typically evaluated in an autosomal dominant context, so recessive trans-occurrence evidence is not applicable here.	pvs1_gene_context
PM4	N/A	This variant does not produce a protein length change such as an in-frame deletion, insertion, or stop-loss.
PM5	N/A	PM5 same-residue missense logic does not apply because this is not a missense variant and no residue-based comparator framework was available for use.	pm5_candidates
PM6	Not assessed	No presumed de novo report with incomplete parental confirmation was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant.	clinvar
PP2	N/A	PP2 is not applicable because this is not a missense variant.
PP3	Not met	Available computational evidence does not support a damaging effect on splicing. SpliceAI predicts no significant splice impact with a max delta score of 0.00, and no REVEL, BayesDel, or HCI prior score was available for this intronic variant.	spliceai
PP4	Not assessed	No phenotype-specific evidence was provided to show a highly specific TSC2-related clinical presentation attributable to this variant.
PP5	N/A	PP5 is not applied because external assertions without independently evaluable evidence are not used as stand-alone support.	clinvar
BA1	Not met	Population frequency does not reach the default BA1 threshold of 1%. The highest observed population frequency was 0.65789% in Amish individuals in gnomAD v4.1, which is below 1%.	gnomad_v4
BS1	Met	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 gnomad_v2 gnomad_canada
BS2	Not assessed	No data were identified showing this variant in definitively unaffected individuals at an evidence level sufficient for BS2.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	No well-established functional study was identified showing normal splicing or preserved TSC2 function for this variant.	clinvar spliceai
BS4	Not assessed	No non-segregation data were identified for this variant.
BP1	N/A	BP1 is a missense-specific criterion and does not apply to this intronic variant.
BP2	Not assessed	No confirmed co-occurrence with another pathogenic variant in a phase context informative for BP2 was identified.	clinvar
BP3	N/A	BP3 is not applicable because this is not an in-frame coding variant in a repetitive region.
BP4	Met	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
BP5	Not assessed	No alternate molecular explanation for phenotype was provided that would support BP5.
BP6	N/A	BP6 is not applied because external assertions without independently evaluable evidence are not used as stand-alone support.	clinvar
BP7	Not assessed	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.	spliceai PMID:31275557

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.