Variant classification summary

NM_000455.5:c.-1C>T

STK11 · NP_000446.1:p.? · NM_000455.5

GRCh37: chr19:1206912 C>T · GRCh38: chr19:1206913 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

2.0951210345072784e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (supporting): grpmax FAF 4.13e-06 (gnomAD v2.1), total AF 1.07e-05-2.10e-05 with zero homozygotes, well below the <=0.0001 rarity threshold.

2

BP4 (supporting): SpliceAI max delta 0.01 on the splice path for this non-missense variant, below the <0.1 cut-off, predicting no impact on splicing.

3

PVS1 (not applicable): c.-1C>T is a 5' UTR substitution upstream of the initiation codon and not a null class, so no very strong pathogenic evidence applies.

4

PS4, PP4, BP5 (not met): no case-control enrichment, no proband phenotype, and no alternative molecular cause are documented for this variant.

5

BA1/BS1/BS2 (not met): maximum population frequency 1.15e-04 is far below the benign frequency thresholds and no homozygotes were observed.

6

PP5/BP6 (not met): ClinVar record 185127 is laboratory-only with 0 expert-panel submissions and conflicting 1-star classifications.

Final determination: Generic ACMG/AMP 2015 fallback rules match no pathogenic, likely pathogenic, benign or likely benign combination threshold for 1 supporting pathogenic (PM2) plus 1 supporting benign (BP4) evidence, so the variant is classified as Variant 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	N/A	Not applicable: c.-1C>T is a 5' UTR base upstream of the initiation codon, not a null type, and SpliceAI max delta 0.01 excludes a splice-null effect.	pvs1_generic_framework pvs1_gene_context spliceai PMID:25741868
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_000455.5:c.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: zero probands with confirmed parental testing are documented, so a de novo occurrence of c.-1C>T cannot be established.	clinvar PMID:25741868
PS3	Not assessed	Not assessed: no minigene, transcript, or protein functional assay has been reported for STK11 c.-1C>T to evaluate a damaging effect.	clinvar spliceai PMID:26467025 PMID:25741868
PS4	Not met	Not met: no case-control enrichment data exist for this variant, and the only STK11 case series does not name c.-1C>T.	PMID:25741868 PMID:25980754
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_000455.5:c.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	Met (supporting): grpmax FAF 4.13e-06 (gnomAD v2.1) is well below the <=0.0001 PM2 rarity threshold.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
PM3	N/A	Not applicable: PM3 is restricted to recessive disorders, and STK11-related Peutz-Jeghers syndrome is an autosomal dominant condition.	PMID:25741868 PMID:35802134
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000455.5:c.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_000455.5:c.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no affected individual with a presumed de novo c.-1C>T and unconfirmed parental testing is documented.	clinvar PMID:25741868
PP1	Not assessed	Not assessed: zero informative meioses and no variant-carrying affected relatives are documented for c.-1C>T.	clinvar PMID:25741868 pvs1_gene_context
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_000455.5:c.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.01, far below the >=0.2 supporting PP3 threshold.	spliceai
PP4	Not met	Not met: no proband phenotype or family history is available to demonstrate disease specificity for this variant.	PMID:25741868 PMID:20301443 PMID:35802134
PP5	Not met	Not met: ClinVar record 185127 has 0 expert-panel submissions and a conflicting, 1-star laboratory-only review status.	clinvar PMID:25741868
BA1	Not met	Not met: maximum population frequency 1.15e-04 (gnomAD v4.1, Remaining individuals) is ~435-fold below the 0.05 BA1 stand-alone threshold.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
BS1	Not met	Not met: highest subpopulation frequency 1.15e-04 (gnomAD v4.1, Remaining individuals) is ~87-fold below the 0.01 BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
BS2	Not met	Not met: zero homozygotes across all gnomAD datasets, and the adult-onset, incompletely penetrant autosomal dominant Peutz-Jeghers phenotype does not satisfy BS2's requirement of full penetrance at an early age.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
BS3	Not assessed	Not assessed: no functional assay reporting normal STK11 c.-1C>T splicing or protein function is available to evaluate BS3.	clinvar spliceai PMID:26467025 PMID:25741868
BS4	Not assessed	Not assessed: no family genotypes are available, so non-segregation of c.-1C>T cannot be demonstrated.	clinvar PMID:25741868 pvs1_gene_context
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_000455.5:c.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second STK11 variant or phasing data exist to establish whether this variant lies in cis or in trans.	PMID:25741868 PMID:35802134 clinvar
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000455.5:c.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI max delta 0.01 versus the <=0.1 BP4 supporting threshold.	spliceai
BP5	Not met	Not met: no case carrying this variant has a documented alternative molecular cause.	PMID:25741868 PMID:25980754
BP6	Not met	Not met: ClinVar record 185127 contains 0 expert-panel submissions; its benign labels are ordinary laboratory assertions.	clinvar PMID:25741868
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000455.5:c.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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