NM_000455.5:c.*16+7C>T

STK11 · NP_000446.1:p.? · NM_000455.5

GRCh37: chr19:1226669 C>T · GRCh38: chr19:1226670 C>T

Gene: STK11 Transcript: NM_000455.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

STK11

Transcript

NM_000455.5

Protein

NP_000446.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The STK11 c.*16+7C>T (p.?) variant has been reported in ClinVar as likely benign by two clinical laboratories, and no expert-panel review was identified.

This variant is present at low frequency in gnomAD, with AF 0.00639% in v2.1 and AF 0.00677% in v4.1; these values remain below the 0.1% PM2 threshold.

In silico splice prediction does not support a damaging effect, with SpliceAI showing a maximum delta score of 0.01, consistent with no significant splice impact.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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	STK11 loss of function is an established disease mechanism, but this variant is a noncanonical c.*16+7C>T change in the terminal noncoding region and does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	This is a noncoding variant with no defined amino acid substitution, so the same-amino-acid-change rule does not apply.
PS2	Not assessed	No confirmed de novo occurrence with parental testing was identified for this variant.	clinvar
PS3	Not assessed	No published functional or RNA study was identified showing that this variant damages STK11 function or splicing.	spliceai
PS4	Not assessed	No enrichment data or series of affected individuals carrying this variant were identified.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	This variant lies in the terminal noncoding region, and no evidence was identified that this position is a mutational hotspot or a well-established critical noncoding element with little benign variation.
PM2	Met	This variant is rare in population databases, with gnomAD v2.1 AF 0.00639% (8/125122) and gnomAD v4.1 AF 0.00677% (101/1490806), both below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4
PM3	N/A	No recessive disease context or trans observations relevant to PM3 were identified for this variant.
PM4	N/A	This variant does not alter protein length or the reading frame.
PM5	N/A	This is not a novel missense change at a residue with another established pathogenic missense variant.
PM6	Not assessed	No probable de novo occurrence was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified showing that this variant tracks with disease in a family.	clinvar
PP2	N/A	PP2 is a missense-based criterion and does not apply to this noncoding variant.
PP3	Not met	Available computational evidence does not support a damaging splice effect. SpliceAI shows a maximum delta score of 0.01, which is below commonly used significance thresholds, and REVEL and BayesDel scores were not available for this noncoding change.	spliceai
PP4	Not assessed	No case-specific phenotype information was identified to determine whether the clinical presentation is highly specific for an STK11-related disorder.
PP5	Not assessed	No independent reputable-source pathogenic assertion suitable for PP5 use was identified.	clinvar
BA1	Not met	The population frequency does not meet the BA1 threshold. The highest observed population frequency is 0.00827% in gnomAD v4.1, which is below the 1% threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The population frequency does not meet the BS1 threshold. The highest observed population frequency is 0.00827% in gnomAD v4.1, which is below the 0.3% threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Population data show heterozygous carriers but no evidence was identified demonstrating observation in healthy adults at a level sufficient for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional or RNA study was identified showing that this variant has no damaging effect on STK11 function or splicing.	spliceai
BS4	Not assessed	No nonsegregation data were identified for this variant.	clinvar
BP1	N/A	BP1 is a missense-based criterion and does not apply to this noncoding variant.
BP2	Not assessed	No phase or co-occurrence data were identified for this variant.	clinvar
BP3	Not assessed	No evidence was identified that this variant lies within a repetitive region or a region without known function where small variation is common.
BP4	Met	Available computational evidence supports no significant impact on splicing. SpliceAI predicts a maximum delta score of 0.01, which is below commonly used splice-impact thresholds; REVEL and BayesDel scores were not available for this noncoding change.	spliceai
BP5	Not assessed	No evidence was identified for an alternate molecular explanation that would make this variant noncontributory to the phenotype.
BP6	Not assessed	ClinVar reports this variant as likely benign, but no independent reputable-source benign assertion without accessible evidence was identified for BP6 use.	clinvar
BP7	N/A	BP7 is intended for synonymous variants, and this variant is a noncoding intronic/UTR change rather than a synonymous substitution.

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.