About KEAP1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KEAP1 c.887G>A, p.(Arg296His)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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Criteria may be applied incorrectly, sources may be misread, and a
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Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BS1Strong
BS1 · strong
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.
BS2Strong
BS2 · strong
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.
BP4Supporting
BP4 · supporting
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.
Recorded classification: Benign
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 strong, BS2 strong, BP4 supporting; combination = 2 strong benign + 1 supporting benign, which maps to Benign.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
331 / 1,614,030 alleles
gnomAD v4.1: 331 / 1,614,030 alleles. Recorded AF 0.000205077. Recorded homozygote count 3.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000396629; MAF= 0.03966%, 112/282380 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00339714; MAF= 0.33971%, 104/30614 alleles, homozygotes = 0); grpmax FAF= 0.00286821.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0002714146129627619, 5/18422 alleles, homozygotes = 0).
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KEAP1, a tumor suppressor and adaptor protein, is recurrently mutated in lung cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 3 met · 16 not met · 2 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
No criteria match.
Met · 3
BS1 StrongThe 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. Details ▾Hide ▴
Evidence considered
- SAS AF 0.34% (v2.1
- 104/30614) and 0.32% (v4.1
- 292/91086) > 0.3% BS1 threshold. 3 homozygotes in gnomAD v4.1.
Sources
BS2 StrongThree 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. Details ▾Hide ▴
Evidence considered
- 3 homozygotes in gnomAD v4.1 (2 SAS_XX females
- 1 SAS_XY male). Incompatible with autosomal dominant fully penetrant disorder.
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL 0.189
- BayesDel -0.262
- SpliceAI max delta 0.00 — all predict benign/no impact.
Sources
Not met · 16 · evaluated, threshold not reached
PS2 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. Details ▾Hide ▴
Evidence considered
- No de novo observations in ClinVar. Literature_pass identified 0 PMIDs across all evidence sources.
Still missing
- No trio or de novo testing data available for this variant.
Sources
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific evidence. Literature_pass: 0 PMIDs across all evidence sources. No functional data for this variant or a systematically characterized range that includes residue 296.
Still missing
- No experimental functional characterization of p.Arg296His or systematic range spanning residue 296.
Sources
PS4 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. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar. gnomAD shows population frequency but no case-control enrichment data.
Still missing
- No case-control studies or affected cohort data available.
Sources
PM1 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. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not significant
- exact variant not listed. No domain-level hotspot established at residue 296.
Still missing
- No published mutational hotspot data for KEAP1 residue 296.
Sources
PM2 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. Details ▾Hide ▴
Evidence considered
- Overall AF 0.04% < 0.1% PM2 threshold
- but SAS AF 0.34% > 0.3% BS1 threshold. 3 homozygotes in gnomAD v4.1.
Sources
PM6 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. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar or literature. 0 PMIDs identified in literature_pass.
Still missing
- No trio or de novo testing data.
Sources
PP1 No co-segregation data is available for this variant. PP1 requires observation of the variant segregating with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No co-segregation studies or family data available for NM_012289.4:c.887G>A.
Still missing
- No family-based segregation analysis.
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL 0.189 (benign-leaning)
- BayesDel -0.262 (benign)
- SpliceAI max delta 0.00 (no splice impact).
Sources
PP4 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. Details ▾Hide ▴
Evidence considered
- No phenotype or clinical data provided for variant-level PP4 assessment.
Still missing
- No clinical phenotype or family history available.
PP5 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. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar. No pathogenic assertion from any reputable source.
Sources
BA1 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. Details ▾Hide ▴
Evidence considered
- SAS max AF 0.34% (v2.1) / 0.32% (v4.1)
- below 1% BA1 threshold.
Sources
BS4 No segregation data is available to demonstrate lack of co-segregation with disease in affected families. Details ▾Hide ▴
Evidence considered
- No family-based segregation analysis available.
Still missing
- No segregation data.
BP1 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. Details ▾Hide ▴
Evidence considered
- Both missense and truncating KEAP1 variants cause disease per PMID:39373520. BP1 criteria not satisfied.
BP2 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. Details ▾Hide ▴
Evidence considered
- No phasing data or co-occurrence observations with known pathogenic KEAP1 variants.
Still missing
- No trans/cis phase data.
BP5 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. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis data available.
Still missing
- No clinical co-occurrence data with alternate molecular diagnoses.
BP6 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. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar. No benign assertion from any source.
Sources
Not assessed · 2 · no assessment recorded
PP2 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. Details ▾Hide ▴
Evidence considered
- Insufficient constraint data to evaluate PP2. gnomAD missense constraint metrics not available.
Still missing
- gnomAD gene constraint metrics (Z-score
- missense o/e) not available for KEAP1.
BS3 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. Details ▾Hide ▴
Evidence considered
- No experimental functional studies of p.Arg296His available. Population evidence (homozygotes) is observational
- not experimental.
Still missing
- No experimental functional characterization of p.Arg296His.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis 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. Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket=other per pvs1_variant_assessment
- PVS1 framework not applicable.
Sources
PS1 N/APS1 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. Details ▾Hide ▴
Evidence considered
- No alternative pathogenic nucleotide change identified at c.887 in ClinVar.
Sources
PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator candidates identified
- pm5_mode=unknown
- eligible_for_classic_pm5_search=false.
Sources
pm5_candidates
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous/non-coding variants.
PS5 N/APS5 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. Details ▾Hide ▴
Evidence considered
- PS5 does not exist in the ACMG/AMP 2015 criteria set (PS1-PS4 and PM1-PM6 are the defined pathogenic criteria).
Sources
generic_acmg_combination_rules
Identifiers
- Gene
- KEAP1
- Transcript
- NM_012289.4
- Coding (HGVS c.)
- NM_012289.4:c.887G>A
- Protein (HGVS p.)
- NP_036421.2:p.(Arg296His)
- GRCh38
- chr19:10492015 C>T
- GRCh37
- chr19:10602691 C>T
Gene diagram
Every interpreted variant in KEAP1, mapped onto the exon structure of NM_012289.4. Select a row to find it on the plot.
KEAP1NM_012289.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in KEAP1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
331 / 1,614,030 alleles
AF 0.000205 · 3 homozygotes · FAF 0.0029
gnomAD v2.1
112 / 282,380 alleles
AF 0.000397 · 0 homozygotes · FAF 0.00287
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00021 · 331 / 1,614,030 alleles · 3 hom · FAF 0.0029
| South Asian292 / 91,086 | 0.00323 hom |
| Middle Eastern1 / 6,062 | 0.00016 |
| Remaining individuals7 / 62,506 | 0.00011 |
| European (non-Finnish)30 / 1,180,032 | 2.5e-05 |
| European (Finnish)1 / 63,866 | 1.6e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, Amish, East Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 0.0004 · 112 / 282,380 alleles · 0 hom · FAF 0.0029
| South Asian104 / 30,614 | 0.0034 |
| European (non-Finnish)8 / 128,838 | 6.2e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000205077; MAF= 0.02051%, 331/1614030 alleles, homozygotes = 3) and has highest observed frequency in the South Asian population (AF= 0.00320576; MAF= 0.32058%, 292/91086 alleles, homozygotes = 3); grpmax FAF= 0.00290293.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000396629; MAF= 0.03966%, 112/282380 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00339714; MAF= 0.33971%, 104/30614 alleles, homozygotes = 0); grpmax FAF= 0.00286821.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0002714146129627619, 5/18422 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.189
- BayesDel
- -0.262
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL 0.189
- BayesDel -0.262
- SpliceAI max delta 0.00 — all predict benign/no impact.
Sources
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL 0.189 (benign-leaning)
- BayesDel -0.262 (benign)
- SpliceAI max delta 0.00 (no splice impact).
Sources
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous/non-coding variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.189. BayesDel score = -0.262097.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
331 / 1,614,030 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_012289.4%3Ac.887G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-10602691-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-10492015-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-10492015-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_012289.4%3Ac.887G…
- OncoKB ↗www.oncokb.org/gene/KEAP1/R296H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=KEAP1+c.887G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000205077; MAF= 0.02051%, 331/1614030 alleles, homozygotes = 3) and has highest observed frequency in the South Asian population (AF= 0.00320576; MAF= 0.32058%, 292/91086 alleles, homozygotes = 3); grpmax FAF= 0.00290293.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000396629; MAF= 0.03966%, 112/282380 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00339714; MAF= 0.33971%, 104/30614 alleles, homozygotes = 0); grpmax FAF= 0.00286821.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0002714146129627619, 5/18422 alleles, homozygotes = 0).
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.189. BayesDel score = -0.262097.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KEAP1, a tumor suppressor and adaptor protein, is recurrently mutated in lung cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.