About KEAP1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KEAP1 c.1222C>A, p.(Pro408Thr)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present in gnomAD at extremely low frequency in population databases: v2.1 AF=3.37e-05 (0.00337%, 7/207,868 alleles, 0 homozygotes) and v4.1 AF=1.08e-05 (0.00108%, 17/1,578,050 alleles, 0 homozygotes). The global allele frequency is well below the 0.1% threshold for PM2 under non-VCEP gnomAD rules. No homozygous individuals have been observed.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple independent lines of computational evidence consistently predict no deleterious impact: REVEL score 0.295 (below the 0.5 pathogenicity threshold, predicting benign), BayesDel score -0.344 (negative score, predicting benign), and SpliceAI maximum delta 0.01 (no predicted splice-altering effect). This concordance across three in silico tools satisfies BP4 at supporting strength.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
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
17 / 1,578,050 alleles
gnomAD v4.1: 17 / 1,578,050 alleles. Recorded AF 1.07728e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.36752e-05; MAF= 0.00337%, 7/207868 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.40631e-05; MAF= 0.00741%, 7/94514 alleles, homozygotes = 0); grpmax FAF= 3.472e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016286644951140066, 3/18420 alleles, homozygotes = 0).
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV105847274, n = 1 times).
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: 2 met · 20 not met · 0 not assessed · 4 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.1222C>A (p.Pro408Thr) in KEAP1 is a rare missense variant present at extremely low frequency in population databases (gnomAD v2.1 AF=0.00337%, v4.1 AF=0.00108%), satisfying PM2 at supporting strength.
Multiple independent in silico tools (REVEL 0.295, BayesDel -0.344, SpliceAI 0.01) consistently predict no deleterious impact on protein function or splicing, satisfying BP4 at supporting strength.
The variant is classified as Uncertain significance by a single clinical laboratory in ClinVar (VCV2209515). No expert panel review is available, and no variant-specific publications or functional studies were identified.
KEAP1 germline mutations cause familial multinodular goiter, with both truncating and missense variants reported as pathogenic (PMID:39373520). Codon 408 falls within the Kelch repeat domain but is not a statistically significant cancer hotspot residue.
Under the generic ACMG/AMP 2015 classification framework (PMID:25741868), the tally is PM2 (supporting pathogenic) + BP4 (supporting benign). With one supporting criterion for each direction, the combined evidence is insufficient to classify as either likely benign or likely pathogenic, resulting in a final classification of Uncertain significance.
No criteria match.
Met · 2
PM2 SupportingThis variant is present in gnomAD at extremely low frequency in population databases: v2.1 AF=3.37e-05 (0.00337%, 7/207,868 alleles, 0 homozygotes) and v4.1 AF=1.08e-05 (0.00108%, 17/1,578,050 alleles, 0 homozygotes). The global allele frequency is well below the 0.1% threshold for PM2 under non-VCEP gnomAD rules. No homozygous individuals have been observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.00337% (7/207
- 868
- 0 homozygotes)
- gnomAD v4.1: AF=0.00108% (17/1
- 578
- 050
- grpmax FAF=3.47e-05 (v2.1)
- 8.14e-06 (v4.1)
Sources
BP4 SupportingMultiple independent lines of computational evidence consistently predict no deleterious impact: REVEL score 0.295 (below the 0.5 pathogenicity threshold, predicting benign), BayesDel score -0.344 (negative score, predicting benign), and SpliceAI maximum delta 0.01 (no predicted splice-altering effect). This concordance across three in silico tools satisfies BP4 at supporting strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.295 (<0.5
- predicts benign)
- BayesDel: -0.344 (negative
- SpliceAI: max delta 0.01 (no splice impact)
Sources
Not met · 20 · evaluated, threshold not reached
PS1 No alternative nucleotide change at codon 408 resulting in the same Pro408Thr amino acid substitution has been reported as pathogenic. No evidence exists to satisfy PS1. Details ▾Hide ▴
Still missing
- No alternative nucleotide changes at codon 408 identified in ClinVar or literature.
PS2 No de novo observation has been reported for this variant. The single ClinVar submission (Ambry Genetics, SCV003527689) did not include parental testing data. Details ▾Hide ▴
PS3 No variant-specific functional studies have been identified for NM_012289.4:c.1222C>A (p.Pro408Thr). OncoKB classifies this variant as Unknown Oncogenic Effect with no curated functional evidence. The COSMIC entry (COSV105847274, n=1) represents a somatic observation count only, not experimental functional data. The codon 408 position falls within the Kelch repeat domain but has not been included in any systematic functional characterization range (e.g., saturation mutagenesis or tiling screen) spanning this residue. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect. COSMIC: single somatic observation
- no functional characterization.
Still missing
- No functional studies testing this variant or a systematically characterized range that includes codon 408.
Sources
PS4 No case-control enrichment data are available. The variant is present in gnomAD at very low frequency (v2.1 AF=0.00337%; v4.1 AF=0.00108%) and has a single ClinVar VUS submission. No statistically significant enrichment in affected individuals has been demonstrated. Details ▾Hide ▴
Evidence considered
- gnomAD: rare but present. ClinVar: single VUS
- no case-control comparison.
Still missing
- No case-control association data available.
Sources
PM1 While codon 408 resides within the Kelch repeat domain of KEAP1 (a well-characterized NRF2-binding domain critical for KEAP1 function), cancerhotspots.org does not identify this residue as a statistically significant hotspot (residue_significant: false). The variant is present in gnomAD (7 alleles v2.1, 17 alleles v4.1), indicating some benign variation exists within this domain. Without a residue-specific hotspot designation and with observed population variation, PM1 is not met under the generic ACMG framework. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: not a significant residue. gnomAD: variant observed in population databases.
Sources
PM5 No different amino acid change at codon 408 has been identified as pathogenic. The automated PM5 candidate search found no qualifying same-residue comparator variants in ClinVar. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic comparator variants found.
Still missing
- No known pathogenic variant at codon 408 with a different amino acid change.
Sources
pm5_candidates
PM6 No de novo observation (confirmed or assumed) has been reported for this variant. PM6 requires at least an assumed de novo event without confirmation of paternity and maternity, which is absent. Details ▾Hide ▴
Still missing
- No de novo data.
PP1 No co-segregation data are available. No family studies involving this variant have been reported. Details ▾Hide ▴
Still missing
- No family segregation data.
PP2 PP2 requires a low rate of benign missense variation in the gene (e.g., high missense Z-score) and missense variants as a common disease mechanism. While KEAP1 germline missense mutations are a known disease mechanism for familial multinodular goiter (PMID:39373520), population constraint metrics (gnomAD missense Z-score or OE ratio) were not available in the evidence packet to confirm a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- KEAP1 missense variants are a known germline disease mechanism for multinodular goiter
- but gene-level constraint data not available.
Still missing
- gnomAD gene constraint metrics (missense Z-score
- OE ratio) not available in evidence packet.
PP3 In silico computational tools do not support a deleterious effect: REVEL score 0.295 (below 0.5 threshold, predicts benign), BayesDel score -0.344 (negative, predicts benign), SpliceAI max delta 0.01 (no predicted splice impact). All three independent computational lines agree that this variant is likely benign, which instead supports BP4. Details ▾Hide ▴
Evidence considered
- REVEL: 0.295 (benign range
- <0.5)
- BayesDel: -0.344 (benign range
- negative score)
- SpliceAI: max delta 0.01 (no splice impact)
Sources
PP4 No patient phenotype or family history data are available to evaluate whether the clinical presentation is highly specific for a KEAP1-related disorder with a single genetic etiology. Details ▾Hide ▴
Still missing
- No proband phenotype or family history provided.
PP5 ClinVar reports this variant as Uncertain significance (1 submitter, criteria provided, single submitter; not an expert panel). The PP5/BP6 rule requires a 3-star expert panel classification for automatic assignment. The single Ambry Genetics submission (SCV003527689) is classified as VUS with no expert panel designation, and does not meet the threshold for PP5 at any strength level. Details ▾Hide ▴
Evidence considered
- ClinVar VCV2209515: VUS
- single submitter (Ambry Genetics)
- not expert panel.
Sources
BA1 The global population allele frequency in gnomAD v2.1 is 0.00337% (AF=3.37e-05) and in v4.1 is 0.00108% (AF=1.08e-05), both far below the BA1 threshold of 1% (>0.01). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.00337%
- v4.1 AF=0.00108% — both <<1% BA1 threshold.
Sources
BS1 The global population allele frequency in gnomAD v2.1 is 0.00337% and in v4.1 is 0.00108%, both well below the BS1 threshold of 0.3% under non-VCEP gnomAD rules. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.00337%
- v4.1 AF=0.00108% — both <<0.3% BS1 threshold.
Sources
BS2 BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. While the variant is present in gnomAD (7–17 heterozygous carriers among presumably healthy population controls), KEAP1 germline disease (familial multinodular goiter) is adult-onset, variably penetrant, and thyroid-specific. Without evidence of early-age full penetrance and given the low allele count, BS2 cannot be reliably applied. No homozygous individuals have been observed. Details ▾Hide ▴
Evidence considered
- gnomAD: 7–17 heterozygous carriers
- 0 homozygotes. KEAP1 goiter: adult-onset
- not fully penetrant at early age.
Still missing
- Penetrance data for KEAP1 germline mutations uncertain.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrating no deleterious effect have been identified for this variant. In silico predictions alone (BP4) do not constitute functional evidence for BS3. Details ▾Hide ▴
Still missing
- No functional studies testing this variant for benign effect.
BS4 No family segregation data are available. BS4 requires lack of segregation with disease in affected family members, which cannot be evaluated for this case. Details ▾Hide ▴
Still missing
- No family segregation data.
BP1 BP1 applies to missense variants in genes where primarily truncating variants cause disease. KEAP1 germline disease (familial multinodular goiter) is caused by both truncating (p.Q86*, p.V411fs) and missense (p.L136P, p.R415C, p.R483H) variants, as demonstrated in PMID:39373520. Missense variants are an established pathogenic mechanism in KEAP1, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- PMID:39373520: KEAP1 germline mutations include both truncating and missense pathogenic variants.
BP2 No data are available regarding observation of this variant in trans with a pathogenic variant or in cis with a pathogenic variant. BP2 cannot be evaluated. Details ▾Hide ▴
Still missing
- No trans/cis phase data.
BP6 ClinVar reports this variant as Uncertain significance, not benign. The PP5/BP6 rule requires a 3-star expert panel classification; the single submitter (Ambry Genetics) classification is VUS with no expert panel designation. BP6 is not met. Details ▾Hide ▴
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_012289.4:c.1222C>A is a missense variant (p.Pro408Thr) and does not fall into the null-variant categories (nonsense, frameshift, canonical ±1,2 splice) required for PVS1 under the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant per PVS1 decision tree.
Sources
BP5 N/ABP5 is not a criterion defined in the ACMG/AMP 2015 sequence variant interpretation guidelines (PMID:25741868) used under the generic_acmg framework. No evidence was assessed under this code. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_012289.4:c.1222C>A is a missense variant (p.Pro408Thr), not a synonymous/silent variant. BP7 applies exclusively to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a criterion defined in the ACMG/AMP 2015 sequence variant interpretation guidelines (PMID:25741868) used under the generic_acmg framework. No evidence was assessed under this code. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- KEAP1
- Transcript
- NM_012289.4
- Coding (HGVS c.)
- NM_012289.4:c.1222C>A
- Protein (HGVS p.)
- NP_036421.2:p.(Pro408Thr)
- GRCh38
- chr19:10491680 G>T
- GRCh37
- chr19:10602356 G>T
- ClinVar
- 2209515
- COSMIC
- COSV105847274
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
17 / 1,578,050 alleles
AF 1.08e-05 · 0 homozygotes · FAF 8.14e-06
gnomAD v2.1
7 / 207,868 alleles
AF 3.37e-05 · 0 homozygotes · FAF 3.47e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.1e-05 · 17 / 1,578,050 alleles · 0 hom · FAF 8.1e-06
| European (non-Finnish)16 / 1,163,148 | 1.4e-05 |
| African/African American1 / 73,896 | 1.4e-05 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 3.4e-05 · 7 / 207,868 alleles · 0 hom · FAF 3.5e-05
| European (non-Finnish)7 / 94,514 | 7.4e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.07728e-05; MAF= 0.00108%, 17/1578050 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.37558e-05; MAF= 0.00138%, 16/1163148 alleles, homozygotes = 0); grpmax FAF= 8.14e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.36752e-05; MAF= 0.00337%, 7/207868 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.40631e-05; MAF= 0.00741%, 7/94514 alleles, homozygotes = 0); grpmax FAF= 3.472e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016286644951140066, 3/18420 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.295
- BayesDel
- -0.344
How the predictions were used
BP4 SupportingMultiple independent lines of computational evidence consistently predict no deleterious impact: REVEL score 0.295 (below the 0.5 pathogenicity threshold, predicting benign), BayesDel score -0.344 (negative score, predicting benign), and SpliceAI maximum delta 0.01 (no predicted splice-altering effect). This concordance across three in silico tools satisfies BP4 at supporting strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.295 (<0.5
- predicts benign)
- BayesDel: -0.344 (negative
- SpliceAI: max delta 0.01 (no splice impact)
Sources
PP3 In silico computational tools do not support a deleterious effect: REVEL score 0.295 (below 0.5 threshold, predicts benign), BayesDel score -0.344 (negative, predicts benign), SpliceAI max delta 0.01 (no predicted splice impact). All three independent computational lines agree that this variant is likely benign, which instead supports BP4. Details ▾Hide ▴
Evidence considered
- REVEL: 0.295 (benign range
- <0.5)
- BayesDel: -0.344 (benign range
- negative score)
- SpliceAI: max delta 0.01 (no splice impact)
Sources
BP7 N/ANM_012289.4:c.1222C>A is a missense variant (p.Pro408Thr), not a synonymous/silent variant. BP7 applies exclusively to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.295. BayesDel score = -0.344485.
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
17 / 1,578,050 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
1 Uncertain significance
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/variation/2209515/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-10602356-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-10491680-G-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-10491680-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_012289.4%3Ac.1222…
- OncoKB ↗www.oncokb.org/gene/KEAP1/P408T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=120365033
- 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= 1.07728e-05; MAF= 0.00108%, 17/1578050 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.37558e-05; MAF= 0.00138%, 16/1163148 alleles, homozygotes = 0); grpmax FAF= 8.14e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.36752e-05; MAF= 0.00337%, 7/207868 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.40631e-05; MAF= 0.00741%, 7/94514 alleles, homozygotes = 0); grpmax FAF= 3.472e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016286644951140066, 3/18420 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2209515)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.295. BayesDel score = -0.344485.
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 previously been reported in somatic cancers (COSMIC; COSV105847274, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.