KEAP1c.445G>AUncertain significance

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Variant interpretation report

KEAP1 c.445G>A, p.(Glu149Lys)

NM_012289.4:c.445G>A NP_036421.2:p.(Glu149Lys) View identifiers

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.

About KEAP1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 supporting (benign) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 26 Jun 2026 · version 7.0.0

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): NM_012289.4:c.445G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the non-VCEP PM2 threshold (allele frequency < 0.1%).
BP4 (supporting): Multiple lines of computational evidence support a benign effect. BayesDel score is 0.0063572, which is strongly predictive of a benign impact. REVEL score is 0.487, below the 0.5 threshold for deleterious prediction. SpliceAI max delta score is 0.00, indicating no splice alteration.

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

NM_012289.4:c.445G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the non-VCEP PM2 threshold (allele frequency < 0.1%).

Benign criteria applied · 1

BP4Supporting

BP4 · supporting

Multiple lines of computational evidence support a benign effect. BayesDel score is 0.0063572, which is strongly predictive of a benign impact. REVEL score is 0.487, below the 0.5 threshold for deleterious prediction. SpliceAI max delta score is 0.00, indicating no splice alteration.

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

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗

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

5 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV50268680, n = 5 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

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 · 11 not met · 1 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_012289.4:c.445G>A (p.Glu149Lys) is a missense variant in KEAP1. This variant has been observed in somatic cancers (COSMIC, n=5) but has not been reported in ClinVar and is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada).

The variant is absent from gnomAD in all assessed populations, meeting PM2 at supporting strength.

Computational evidence supports a benign effect: BayesDel score of 0.0063572 strongly predicts benign, REVEL score of 0.487 is below the pathogenic threshold, and SpliceAI predicts no splice alteration (max delta 0.00). BP4 is met at supporting strength.

No functional studies, case-control data, de novo observations, segregation data, or ClinVar classifications are available for this variant. No published literature (PMIDs) was identified that directly mentions NM_012289.4:c.445G>A.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is insufficient to classify this variant as either likely pathogenic or likely benign under generic ACMG/AMP 2015 rules. The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 2

PM2 SupportingNM_012289.4:c.445G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the non-VCEP PM2 threshold (allele frequency < 0.1%). Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 exomes
Absent from gnomAD v4.1 exomes
Absent from gnomAD-Canada v1.0 genomes

Still missing

gnomAD v2.1 genomes not separately assessed
but exome coverage expected sufficient for KEAP1 coding region

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP4 SupportingMultiple lines of computational evidence support a benign effect. BayesDel score is 0.0063572, which is strongly predictive of a benign impact. REVEL score is 0.487, below the 0.5 threshold for deleterious prediction. SpliceAI max delta score is 0.00, indicating no splice alteration. Details ▾Hide ▴

Evidence considered

BayesDel: 0.0063572 (predicts benign)
REVEL: 0.487 (neutral
below pathogenicity threshold)
SpliceAI max delta: 0.00 (no splicing impact)

Sources

revelbayesdelspliceai ↗

Not met · 11 · evaluated, threshold not reached

PS1 No evidence of a different nucleotide change at codon 149 resulting in the same amino acid substitution (p.Glu149Lys) with established pathogenicity. No ClinVar entries at this residue were identified. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar
no comparator variants at codon 149

Still missing

No ClinVar entries at Glu149 with established pathogenicity

Sources

clinvar ↗

PS3 No well-established functional studies identified for this variant. OncoKB classifies NM_012289.4:c.445G>A (p.E149K) as 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. No PMIDs citing functional data for this variant were found. Details ▾Hide ▴

Evidence considered

OncoKB: Unknown Oncogenic Effect
no variant-specific functional evidence

Still missing

No functional studies for p.E149K in KEAP1

Sources

oncokb ↗

PM1 Codon 149 is not located in a statistically significant mutational hotspot in KEAP1. Cancer Hotspots analysis confirmed this residue is not significant. Details ▾Hide ▴

Evidence considered

Cancer Hotspots: residue not significant
exact variant not listed

PM5 No same-residue (Glu149) comparator missense variants with established pathogenicity were identified in ClinVar. The PM5 candidate harvesting pipeline found zero candidates and marked PM5 as not applicable for this variant. Details ▾Hide ▴

Evidence considered

No ClinVar entries at Glu149 with pathogenic classification

Still missing

No ClinVar comparator variants at codon 149

Sources

pm5_candidatesclinvar ↗

PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.487 (below the 0.5 threshold for pathogenicity) and BayesDel score is 0.0063572, which strongly predicts a benign effect. SpliceAI max delta score is 0.00, indicating no splicing impact. Details ▾Hide ▴

Evidence considered

REVEL: 0.487 (neutral
below 0.5 deleterious threshold)
BayesDel: 0.0063572 (predicts benign)
SpliceAI max delta: 0.00 (no splice impact)

Sources

revelbayesdelspliceai ↗

PP5 No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar; OncoKB classifies it as 'Unknown Oncogenic Effect.' Details ▾Hide ▴

Evidence considered

ClinVar: absent
OncoKB: Unknown Oncogenic Effect

Still missing

No expert panel or reputable source classification

Sources

clinvar ↗oncokb ↗

BA1 NM_012289.4:c.445G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the BA1 threshold (allele frequency > 1% per non-VCEP cutoff). Details ▾Hide ▴

Evidence considered

Absent from all gnomAD datasets
allele frequency 0.0%

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 NM_012289.4:c.445G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the non-VCEP BS1 threshold (allele frequency > 0.3%). Details ▾Hide ▴

Evidence considered

Absent from all gnomAD datasets
allele frequency 0.0%

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS3 No well-established functional studies demonstrating no damaging effect for this variant. No functional data for p.E149K were identified. Details ▾Hide ▴

Evidence considered

OncoKB: Unknown Oncogenic Effect
no variant-specific functional evidence

Still missing

No functional studies for KEAP1 p.E149K

Sources

oncokb ↗

BP1 KEAP1-associated familial multinodular goiter is caused by both truncating and missense variants (PMID:39373520 reports p.Q86*, p.L136P, p.V411fs, p.R415C, p.R483H). Missense variants are a known mechanism of disease in KEAP1, so BP1 (missense in a gene where primarily truncating variants cause disease) does not apply. Details ▾Hide ▴

Evidence considered

KEAP1 germline disease: both missense (p.L136P
p.R415C
p.R483H) and truncating (p.Q86*
p.V411fs) variants reported as pathogenic

BP6 No reputable source has classified this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴

Evidence considered

ClinVar: variant absent
no benign classification from any source

Sources

clinvar ↗

Not assessed · 1 · no assessment recorded

PP2 KEAP1 is not included in the HCI prior database; no gene-level missense constraint metrics (z-score, missense intolerance score) are available to assess whether KEAP1 has a low rate of benign missense variation. PP2 cannot be evaluated without these data. Details ▾Hide ▴

Evidence considered

HCI prior: gene not supported
no missense constraint data available

Still missing

KEAP1 not in HCI prior database
no gnomAD missense constraint (Z-score) retrieved for PP2 assessment

Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/ANM_012289.4:c.445G>A (p.Glu149Lys) is a missense substitution and does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable for missense variants under PMC6185798. Details ▾Hide ▴

Evidence considered

Missense substitution (E149K)
variant bucket: other
apply_generic_pvs1_framework: false

Sources

pvs1_generic_framework ↗pvs1_variant_assessment

PS2 N/ANo de novo data available; no family studies or parental testing reported for this variant. Details ▾Hide ▴

Still missing

No de novo or trio data

PS4 N/ANo case-control studies or prevalence data available for this variant in affected versus unaffected populations. Details ▾Hide ▴

Still missing

No case-control data for KEAP1 p.E149K

PM6 N/ANo de novo observation reported for this variant. PM6 requires a de novo finding (with or without confirmed maternity/paternity, depending on strength level). Details ▾Hide ▴

Still missing

No de novo data

PP1 N/ANo co-segregation data available. No family studies have been reported for KEAP1 p.E149K. Details ▾Hide ▴

Still missing

No family or co-segregation data

PP4 N/ANo patient phenotype or clinical data provided. PP4 requires that the patient's phenotype or family history is highly specific for the gene/disease. Details ▾Hide ▴

Still missing

No patient phenotype data available

BS2 N/ANo data on observation of this variant in healthy adults with full penetrance expected. BS2 requires observation in a healthy adult individual for a fully penetrant disorder. Details ▾Hide ▴

Still missing

No healthy adult observation data

BS4 N/ANo segregation data available. BS4 requires lack of segregation in affected family members. Details ▾Hide ▴

Still missing

No family or segregation data

BP2 N/ANo data on observation of this variant in trans with a pathogenic variant. BP2 is not assessable. Details ▾Hide ▴

Still missing

No trans phase data

BP5 N/ANo data indicating this variant was found in a case with an alternate molecular basis for disease. BP5 cannot be assessed. Details ▾Hide ▴

Still missing

No alternate molecular cause data

BP7 N/ANM_012289.4:c.445G>A is a missense variant (p.Glu149Lys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

Missense substitution
not synonymous

PS5 N/APS5 is not a criterion in the standard ACMG/AMP 2015 framework (PMID:25741868). Not applicable. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: KEAP1
Transcript: NM_012289.4
Coding (HGVS c.): NM_012289.4:c.445G>A
Protein (HGVS p.): NP_036421.2:p.(Glu149Lys)
GRCh38: chr19:10499589 C>T
GRCh37: chr19:10610265 C>T
COSMIC: COSV50268680

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 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.010

Other predictors

REVEL: 0.487
BayesDel: 0.006

How the predictions were used

Evidence considered

BayesDel: 0.0063572 (predicts benign)
REVEL: 0.487 (neutral
below pathogenicity threshold)
SpliceAI max delta: 0.00 (no splicing impact)

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL: 0.487 (neutral
below 0.5 deleterious threshold)
BayesDel: 0.0063572 (predicts benign)
SpliceAI max delta: 0.00 (no splice impact)

Sources

revelbayesdelspliceai ↗

BP7 N/ANM_012289.4:c.445G>A is a missense variant (p.Glu149Lys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

Missense substitution
not synonymous

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.487. BayesDel score = 0.0063572.

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 Captured gnomAD v4.1 source record 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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 = 0.487. BayesDel score = 0.0063572.

Functional

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV50268680, n = 5 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.