NM_000455.5:c.920+12C>T

STK11 · NP_000446.1:p.? · NM_000455.5

GRCh37: chr19:1222017 C>T · GRCh38: chr19:1222018 C>T

Gene: STK11 Transcript: NM_000455.5

Final call

VUS

BP4 supporting

Variant details

Gene

STK11

Transcript

NM_000455.5

Protein

NP_000446.1:p.?

gnomAD AF

2.5564528705131058e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000455.5:c.920+12C>T is an intronic variant in STK11 located 12 base pairs downstream of exon 7.

This variant is present in gnomAD at low frequency across multiple populations (0.006% overall in v2.1, 0.003% in v4.1), with the highest subpopulation frequency of 0.046% in the African/African American population, indicating it is a rare but known variant and not absent from population databases.

SpliceAI predicts no splicing impact (max delta score = 0.00), providing computational evidence against a deleterious splicing effect for this intronic variant (BP4_supporting).

ClinVar classifies this variant as Likely benign based on 4 clinical laboratory submissions, though the review status is 1-star (criteria provided, single submitter), which does not reach the expert panel threshold for BP6 application.

No functional studies, de novo reports, segregation data, case-control studies, or variant-specific literature are available for this variant. The variant has not been reported in COSMIC and is not listed as a cancer hotspot.

Based on the available evidence, only BP4 (supporting benign) is met. The overall evidence is insufficient to classify this variant as benign or likely benign; the variant remains a variant of uncertain significance (VUS) with a single supporting benign criterion.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, 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	This intronic variant (c.920+12C>T) does not fall into the default null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants, and SpliceAI predicts no splicing impact (max delta = 0.00). PVS1 is not applicable.	pvs1_variant_assessment pvs1_gene_context spliceai
PS1	N/A	This intronic variant does not alter the coding sequence; PS1 requires an established pathogenic variant producing the same amino acid change, which is not applicable for a non-coding variant.
PS2	Not met	No de novo occurrence data with confirmed parentage is available for this variant.
PS3	Not met	No functional studies have been reported for NM_000455.5:c.920+12C>T. Neither the exact variant nor a systematically characterized range encompassing this intronic position has been functionally assessed in the literature.
PS4	Not met	No case-control studies or patient cohort data demonstrating enrichment of this variant in affected individuals are available. No publications report this variant in disease-affected individuals.
PS5	Not met	ClinVar reports this variant as Likely benign, not pathogenic. No reputable source has classified this variant as pathogenic.	clinvar
PM1	Not met	This intronic variant (c.920+12C>T) is not located in a known mutational hotspot or critical functional domain. Cancerhotspots.org identifies no residue-level significance for this position, and the variant lies outside the STK11 protein-coding region.
PM2	Not met	This variant is present in gnomAD at low frequency across multiple populations (12/201,762 alleles in v2.1, AF = 0.006%; 40/1,564,668 alleles in v4.1, AF = 0.003%). While below the 0.1% PM2 threshold, the variant is observed in the African/African American population at 0.046% (34/73,732 alleles in v4.1), indicating it is not absent from population databases and is a known rare variant rather than a novel absent variant.	gnomad_v2 gnomad_v4
PM5	N/A	This intronic variant has no predicted protein consequence (NP_000446.1:p.?); PM5 requires a different missense change at the same residue previously classified as pathogenic, which cannot be assessed for a non-coding variant.	pm5_candidates
PM6	Not met	No de novo occurrence data (without confirmed parentage) is available for this variant.
PP1	Not met	No co-segregation data with disease in affected family members is available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation; this is an intronic variant and does not meet the criterion scope.
PP3	Not met	No in silico prediction tools support a deleterious effect. REVEL and BayesDel scores are unavailable for this non-coding variant, and SpliceAI predicts no splicing impact (max delta score = 0.00). No computational evidence supports pathogenicity.	spliceai
PP4	Not met	No patient-specific phenotype data or clinical information is available for assessment of this variant.
PP5	Not met	ClinVar reports this variant as Likely benign with a review status of 'criteria provided, single submitter' (1-star). PP5 requires a reputable source to have classified the variant as pathogenic, which is not the case. The ClinGen expert panel (3-star) threshold required for PP5 application is not met.	clinvar
BA1	Not met	The highest observed allele frequency is 0.046% in the African/African American population (gnomAD v4.1), well below the BA1 threshold of 1%. This variant is too rare to be considered a common benign polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	The highest observed allele frequency is 0.046% in the African/African American population (gnomAD v4.1), below the BS1 threshold of 0.3%. The variant is not sufficiently common to apply BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No data on well-phenotyped healthy adults harboring this variant are available. While the variant is observed in gnomAD (a population database of individuals not selected for disease), the number of observations (12-40 alleles) is insufficient to confidently assert observation in healthy adults with full penetrance expected at an early age for Peutz-Jeghers syndrome.
BS3	Not met	No well-established functional studies demonstrating no deleterious effect are available for this variant. SpliceAI predicts no splicing impact (max delta = 0.00), which is evaluated under BP4 rather than BS3.
BS4	Not met	No segregation data are available to demonstrate lack of co-segregation with disease in affected families.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease; this is an intronic variant and does not fall within BP1 scope.
BP2	Not met	No data on observation of this variant in trans with a known pathogenic variant in a recessive disorder are available. STK11-related Peutz-Jeghers syndrome is autosomal dominant, further limiting BP2 applicability.
BP4	Met	SpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00). For a variant located at intron position +12 from exon 7, where altered splicing would be the primary plausible disease mechanism, this computational evidence supports a benign interpretation. No other in silico predictors contradict this finding.	spliceai
BP5	Not met	No cases have been reported in which this variant is found in a patient with an alternate molecular basis for disease.
BP6	Not met	ClinVar classifies this variant as Likely benign based on 4 clinical laboratory submissions (GeneDx, Mendelics, Color Health, Invitae), but the review status is 'criteria provided, single submitter' (1-star). This does not meet the 3-star expert panel threshold required for BP6 application at supporting strength.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing algorithms predict no impact to the splice consensus sequence; this is an intronic variant, not a synonymous coding variant.

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.