NM_012289.4:c.887G>A

KEAP1 · NP_036421.2:p.(Arg296His) · NM_012289.4

GRCh37: chr19:10602691 C>T · GRCh38: chr19:10492015 C>T

Gene: KEAP1 Transcript: NM_012289.4

Final call

Benign

BS1 strong BS2 strong BP4 supporting

Variant details

Gene

KEAP1

Transcript

NM_012289.4

Protein

NP_036421.2:p.(Arg296His)

gnomAD AF

0.00020507673339405092 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_012289.4:c.887G>A (p.Arg296His) is present in the South Asian population at an allele frequency of 0.34% (gnomAD v2.1: 104/30,614 alleles) and 0.32% (gnomAD v4.1: 292/91,086 alleles), exceeding the 0.3% threshold for BS1.

Three homozygous individuals for c.887G>A are observed in gnomAD v4.1 (2 female, 1 male, all South Asian), which is incompatible with a fully penetrant autosomal dominant disorder such as KEAP1-related familial multinodular goiter (PMID:39373520).

Multiple in silico tools predict a benign effect: REVEL score 0.189 (below pathogenicity threshold), BayesDel score -0.262 (benign), and SpliceAI max delta 0.00 (no splice impact).

The variant is absent from ClinVar with no disease-associated submissions, and absent from COSMIC with no somatic cancer reports.

Computational evidence (BP4) and strong population evidence (BS1, BS2: elevated subpopulation frequency and homozygous observations) collectively support a Benign classification per ACMG/AMP 2015 rules: two strong benign criteria (BS1 + BS2) meet the threshold for Benign.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong 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	N/A	This is a missense variant (c.887G>A, p.Arg296His). The ClinGen SVI PVS1 recommendations (PMC6185798) restrict PVS1 to null variant types (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, single/multi-exon deletions). Missense variants are not eligible for PVS1.	pvs1_generic_framework
PS1	N/A	PS1 requires a different nucleotide change at the same codon with established pathogenicity. No alternative nucleotide change at KEAP1 c.887 has been reported as pathogenic in ClinVar or the literature.	clinvar
PS2	Not met	No de novo occurrence has been reported for NM_012289.4:c.887G>A in any publication or clinical database. De novo evidence is absent.	clinvar
PS3	Not met	No functional studies have tested NM_012289.4:c.887G>A (p.Arg296His) directly, nor is residue 296 encompassed by a systematically characterized range (e.g., saturation mutagenesis, CRISPR tiling screen, systematic truncation series) in the published literature. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional evidence. Domain-level inference from sparse testing of nearby residues does not satisfy PS3 requirements.	oncokb
PS4	Not met	No case-control or cohort data comparing variant prevalence in affected versus general population is available. The variant is absent from ClinVar with no disease-associated submissions identified.	clinvar gnomad_v2 gnomad_v4
PS5	N/A	PS5 is not a defined criterion in the ACMG/AMP 2015 framework (PMID:25741868). No standard definition exists for this criterion in the generic ACMG/AMP classification rules.	generic_acmg_combination_rules
PM1	Not met	Residue 296 (p.Arg296) lies within the KEAP1 IVR (intervening region, aa 180-314), which contains redox-sensitive cysteine residues. However, cancerhotspots.org reports no statistically significant hotspot at this residue, and no published data establish this specific residue as a critical functional domain hotspot. The IVR as a whole is not classified as a well-characterized mutational hotspot domain for PM1 purposes.	oncokb
PM2	Not met	Overall gnomAD allele frequency (0.04% v2.1, 0.021% v4.1) is below the 0.1% PM2 threshold. However, the South Asian subpopulation frequency is 0.34% (v2.1) and 0.32% (v4.1), which exceeds the 0.3% BS1 threshold. Additionally, 3 homozygotes are observed in gnomAD v4.1. The elevated subpopulation frequency and homozygous observations indicate this is a population polymorphism, negating PM2 in favor of BS1/BS2.	gnomad_v2 gnomad_v4
PM5	N/A	No pathogenic same-residue comparator variants were identified to satisfy PM5 semantics. The pm5_candidates.json automated search found zero candidates at the same residue position. PM5 cannot be applied without a confirmed pathogenic variant at the same amino acid position.	pm5_candidates
PM6	Not met	No de novo occurrence data for NM_012289.4:c.887G>A is available. PM6 requires confirmed de novo parentage with no family history. No publications or clinical databases report de novo status for this variant.	clinvar
PP1	Not met	No co-segregation data is available for this variant. PP1 requires observation of the variant segregating with disease in multiple affected family members.
PP2	Not assessed	PP2 requires a low rate of benign missense variation in the gene and missense variants as a common disease mechanism. No gnomAD constraint metrics (Z-score, missense o/e ratio) are available in the evidence to determine whether KEAP1 has a low rate of benign missense variation. While KEAP1 missense variants are a known disease mechanism (PMID:39373520), population data for this variant suggests benign missense variation exists in KEAP1.
PP3	Not met	Multiple lines of computational evidence predict a benign effect. REVEL score 0.189 is below the 0.5 threshold for pathogenicity. BayesDel score -0.262 is negative, predicting benign. SpliceAI max delta score is 0.00, predicting no splice alteration. In silico evidence uniformly supports a benign interpretation.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data is available for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	No reputable source has reported NM_012289.4:c.887G>A as pathogenic. The variant is absent from ClinVar entirely; there are no submissions, classifications, or expert panel reviews available.	clinvar
BA1	Not met	The highest subpopulation allele frequency is 0.34% in South Asians (gnomAD v2.1). This is below the 1% threshold for BA1 (stand-alone benign). The variant is not common enough in any population to be considered a stand-alone benign polymorphism by BA1 criteria.	gnomad_v2 gnomad_v4
BS1	Met	The South Asian subpopulation allele frequency is 0.34% in gnomAD v2.1 (104/30,614 alleles) and 0.32% in gnomAD v4.1 (292/91,086 alleles), exceeding the 0.3% BS1 threshold. This frequency is incompatible with a high-penetrance pathogenic variant for familial multinodular goiter or other KEAP1-related Mendelian disorder. Additionally, 3 homozygotes are observed in gnomAD v4.1, further confirming the variant is too common in the general population to be pathogenic.	gnomad_v2 gnomad_v4
BS2	Met	Three homozygotes for NM_012289.4:c.887G>A (p.Arg296His) are observed in gnomAD v4.1 (2 female, 1 male, all within the South Asian population). KEAP1 germline mutations cause autosomal dominant familial multinodular goiter (PMID:39373520). Observation of homozygous individuals in a population database is incompatible with a fully penetrant autosomal dominant disorder, strongly supporting a benign interpretation.	gnomad_v4
BS3	Not assessed	No well-established in vitro or in vivo functional studies have tested NM_012289.4:c.887G>A for damaging effect. While the presence of 3 homozygotes in gnomAD strongly suggests no severe damaging effect in vivo, BS3 requires experimental functional data demonstrating no impact on protein function, which is not available.
BS4	Not met	No segregation data is available to demonstrate lack of co-segregation with disease in affected families.
BP1	Not met	BP1 applies when a missense variant occurs in a gene for which primarily truncating variants cause disease. KEAP1 germline disease includes both missense (p.L136P, p.R415C, p.R483H) and truncating (p.Q86*, p.V411fs) variants as established causes of familial multinodular goiter (PMID:39373520). Since missense variants are an established disease mechanism, BP1 does not apply.
BP2	Not met	No data available on whether this variant has been observed in trans with a pathogenic KEAP1 variant. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern.
BP4	Met	Multiple lines of computational evidence predict a benign effect. REVEL score 0.189 (below 0.5 pathogenicity threshold), BayesDel score -0.262 (negative, predicting benign), and SpliceAI max delta score 0.00 (predicting no splice impact). Three independent in silico tools uniformly support a neutral/benign interpretation.	revel bayesdel spliceai
BP5	Not met	No data available demonstrating that this variant has been observed in a case with an alternate molecular basis for disease. BP5 requires a confirmed alternative genetic cause in a case harboring this variant.
BP6	Not met	No reputable source has reported NM_012289.4:c.887G>A as benign. The variant is absent from ClinVar with no benign classifications from any submitter.	clinvar
BP7	N/A	BP7 applies exclusively to synonymous variants for which splicing prediction algorithms predict no impact on the splice consensus sequence. NM_012289.4:c.887G>A is a missense variant (p.Arg296His), not a synonymous variant, and therefore BP7 is not applicable regardless of splice prediction results.

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