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KEAP1
Final classification
VUS
KEAP1 c.445G>A · p.Glu149Lys
KEAP1

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).

Gene
KEAP1
Transcript
NM_012289.4
HGVS · transcript:coding
NM_012289.4:c.445G>A
Consequence
N/A
GRCh38
chr19:10499589 C>T
GRCh37
chr19:10610265 C>T
Basis 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.
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.
Classification rationale
PM2 BP4 VUS
KEAP1 c.445G>A

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).1 The variant is absent from gnomAD in all assessed populations, meeting PM2 at supporting strength.2 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.3 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.4 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).5

PM2 + BP4 VUS
Gene diagram · NM_012289.4 · variants mapped to exon structure
KEAP1 NM_012289.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 12 assessed
Applied · 2
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
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%).
Absent from gnomAD v2.1 exomesAbsent from gnomAD v4.1 exomesAbsent from gnomAD-Canada v1.0 genomes
BP4 supporting Benign
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.
BayesDel: 0.0063572 (predicts benign)REVEL: 0.487 (neutralbelow pathogenicity threshold)
Assessed · not applied
Pathogenic
PS1 No evidence of a different nucleotide change at codon 149 resulting in the same amino acid substitution (p.Glu149Lys) with established pathogenicity.
PS3 No well-established functional studies identified for this variant.
PM1 Codon 149 is not located in a statistically significant mutational hotspot in KEAP1.
PM5 No same-residue (Glu149) comparator missense variants with established pathogenicity were identified in ClinVar.
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.
PP3 Multiple in silico predictors do not support a deleterious effect.
PP5 No reputable source has classified this variant as pathogenic.
Benign
BA1 NM_012289.4:c.445G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1 NM_012289.4:c.445G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS3 No well-established functional studies demonstrating no damaging effect for this variant.
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).
BP6 No reputable source has classified this variant as benign.
N/A · 11 PVS1 · PS2 · PS4 · PM6 · PP1 · PP4 · BS2 · BS4 · BP2 · BP5 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
SpliceAI screenshot
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 / OncoKB screenshot
Functional Unknown Oncogenic Effect
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.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV50268680, n = 5 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots