About CBL
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CBL c.1240C>A, p.(Gln414Lys)
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
NM_005188.3:c.1240C>A is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada v1.0), meeting the PM2 threshold of <0.1% allele frequency in large population cohorts.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence predict no damaging impact on the gene product. BayesDel score is 0.052 (strongly predictive of benign effect) and SpliceAI max delta score is 0.07 (no predicted splicing impact).
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 benign; 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.
SpliceAI score
0.070 maximum delta
Recorded SpliceAI maximum delta score: 0.070. 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. CBL, a tumor suppressor and ubiquitin ligase, is inactivated by mutation or deletion in various cancer types including myeloid malignancies.
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: 2 met · 22 not met · 0 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_005188.3:c.1240C>A (p.Gln414Lys) is a missense variant in CBL, a gene associated with RASopathies and myeloid malignancies through loss-of-function and missense mechanisms.
This variant is absent from all large population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at supporting level.
Multiple lines of computational evidence (BayesDel 0.052, SpliceAI max delta 0.07) predict no damaging impact on the gene product, meeting BP4 at supporting_benign level.
No functional studies, case reports, segregation data, or literature evidence specific to this variant were identified. The variant is absent from ClinVar and has not been classified by any external source.
With one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP4_Supporting), the evidence is insufficient to classify this variant as either pathogenic or benign. The variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.
No criteria match.
Met · 2
PM2 SupportingNM_005188.3:c.1240C>A is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada v1.0), meeting the PM2 threshold of <0.1% allele frequency in large population cohorts. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes/genomes).
- Absent from gnomAD-Canada v1.0 (genomes).
Sources
BP4 SupportingMultiple lines of computational evidence predict no damaging impact on the gene product. BayesDel score is 0.052 (strongly predictive of benign effect) and SpliceAI max delta score is 0.07 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- BayesDel: 0.052 (predicts benign).
- SpliceAI max delta: 0.07 (no splicing impact
- well below 0.1 threshold).
Sources
bayesdelspliceai ↗
Not met · 22 · evaluated, threshold not reached
PVS1 NM_005188.3:c.1240C>A is a missense variant (p.Gln414Lys) and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants per the ClinGen SVI PVS1 framework (PMC6185798). The variant-level assessment confirms bucket='other' and apply_generic_pvs1_framework=false. Details ▾Hide ▴
Evidence considered
- Missense substitution (Q414K)
- not a null variant.
- PVS1 variant assessment confirms bucket='other' and generic PVS1 framework does not apply.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 No pathogenic variant with the same amino acid change (Q414K) arising from a different nucleotide substitution has been identified in ClinVar or the literature. Without a comparator, PS1 cannot be applied. Details ▾Hide ▴
Evidence considered
- ClinVar contains no entries for this variant or any alternative nucleotide change producing Q414K.
Still missing
- No pathogenic comparator at residue 414 identified.
Sources
PS2 No de novo observation has been reported for this variant in any database or publication. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no de novo submissions identified.
Still missing
- No de novo testing data available.
Sources
PS3 No well-established in vitro or in vivo functional studies have been identified for this variant. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional studies.
- Variant not in COSMIC
- no somatic functional data.
Still missing
- No functional studies (in vitro or in vivo) identified for Q414K.
Sources
PS4 No case-control or prevalence data available. The variant is absent from ClinVar and has not been reported in affected individuals. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar (no case reports).
- Variant absent from gnomAD population databases.
Still missing
- No affected-individual data available.
Sources
PM1 This variant does not lie in a statistically significant mutational hotspot per CancerHotspots.org analysis, and no domain-level functional evidence establishing Q414 as a critical residue was identified in the available data sources. Details ▾Hide ▴
Evidence considered
- CancerHotspots: residue not in a statistically significant hotspot.
- No domain-specific functional annotation for Q414 in available evidence.
Still missing
- No CBL domain-specific annotation in evidence brief.
PM5 No pathogenic missense variant at the same amino acid residue (Q414) was identified in ClinVar. The PM5 candidate search returned zero same-residue comparators. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates.
- ClinVar: no entries at residue 414.
Still missing
- No pathogenic missense comparator at Q414 identified.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation (with or without confirmed maternity/paternity) has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No de novo submissions in ClinVar.
Still missing
- No de novo testing data available.
Sources
PP1 No co-segregation data are available for this variant in affected families. Details ▾Hide ▴
Evidence considered
- No family or co-segregation studies identified.
Still missing
- No family studies available.
PP2 No HCI prior or gene-specific missense constraint metric is available for CBL to support PP2. The HCI prior lookup returned 'gene_not_supported'. Details ▾Hide ▴
Evidence considered
- HCI prior: gene not supported.
- No missense constraint data available.
Still missing
- No missense constraint metric for CBL.
PP3 In silico predictions are mixed and do not reach a consensus of damaging effect. REVEL score is 0.596 (modestly elevated but below conventional PP3 thresholds of 0.7–0.75), while BayesDel score is 0.052 (predicts benign) and SpliceAI max delta is 0.07 (no splice impact). Details ▾Hide ▴
Evidence considered
- REVEL: 0.596 (modest elevation
- below 0.7 threshold).
- BayesDel: 0.052 (strongly predicts benign).
- SpliceAI max delta: 0.07 (no splice impact).
Still missing
- No consensus of damaging in silico predictions.
Sources
PP4 No phenotype or clinical data are available for this variant to assess phenotypic specificity. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data available for this variant.
Still missing
- No phenotype data.
PP5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- No ClinVar submissions.
Still missing
- No external pathogenic classification.
Sources
BA1 Variant is absent from all gnomAD populations; allele frequency is 0% and does not exceed the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD AF = 0% across all populations.
Sources
BS1 Variant is absent from all gnomAD populations; allele frequency is 0% and does not exceed the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD AF = 0% across all populations.
Sources
BS2 No observation of this variant in a healthy adult individual has been reported; the variant is absent from all population databases, precluding assessment of BS2. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- no healthy adult carriers identified.
Still missing
- No carrier data in healthy populations.
Sources
BS3 No well-established functional studies demonstrating a neutral or non-damaging effect have been identified for this variant. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional studies identified.
Still missing
- No functional studies available.
Sources
BS4 No segregation data in affected families are available to assess lack of co-segregation with disease. Details ▾Hide ▴
Evidence considered
- No family segregation studies identified.
Still missing
- No family data.
BP2 No evidence that this variant has been observed in trans with a known pathogenic CBL variant. Details ▾Hide ▴
Evidence considered
- No phase data or trans observations available.
Still missing
- No trans configuration data.
BP5 No case has been identified in which this variant is present alongside an alternative molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No cases with alternative molecular etiology identified.
Still missing
- No co-occurrence data.
BP6 No reputable source has classified this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- No ClinVar submissions
- no benign classification from any source.
Still missing
- No external benign classification.
Sources
PS5 No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- No ClinVar submissions for this variant.
Still missing
- No external classification available.
Sources
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
BP1 N/ACBL is not a gene where only truncating variants cause disease; pathogenic missense variants in CBL are well-established in RASopathies and myeloid malignancies. Details ▾Hide ▴
Evidence considered
- CBL has established pathogenic missense variants
- loss-of-function and missense mechanisms both contribute to disease.
Sources
pvs1_gene_context
BP7 N/ANM_005188.3:c.1240C>A is a missense variant (p.Gln414Lys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is missense (Q414K)
- not synonymous.
Identifiers
- Gene
- CBL
- Transcript
- NM_005188.3
- Coding (HGVS c.)
- NM_005188.3:c.1240C>A
- Protein (HGVS p.)
- NP_005179.2:p.(Gln414Lys)
- GRCh38
- chr11:119278522 C>A
- GRCh37
- chr11:119149232 C>A
Gene diagram
Every interpreted variant in CBL, mapped onto the exon structure of NM_005188.3. Select a row to find it on the plot.
CBLNM_005188.3
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 CBL
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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
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
Other predictors
- REVEL
- 0.596
- BayesDel
- 0.052
How the predictions were used
BP4 SupportingMultiple lines of computational evidence predict no damaging impact on the gene product. BayesDel score is 0.052 (strongly predictive of benign effect) and SpliceAI max delta score is 0.07 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- BayesDel: 0.052 (predicts benign).
- SpliceAI max delta: 0.07 (no splicing impact
- well below 0.1 threshold).
Sources
bayesdelspliceai ↗
PP3 In silico predictions are mixed and do not reach a consensus of damaging effect. REVEL score is 0.596 (modestly elevated but below conventional PP3 thresholds of 0.7–0.75), while BayesDel score is 0.052 (predicts benign) and SpliceAI max delta is 0.07 (no splice impact). Details ▾Hide ▴
Evidence considered
- REVEL: 0.596 (modest elevation
- below 0.7 threshold).
- BayesDel: 0.052 (strongly predicts benign).
- SpliceAI max delta: 0.07 (no splice impact).
Still missing
- No consensus of damaging in silico predictions.
Sources
BP7 N/ANM_005188.3:c.1240C>A is a missense variant (p.Gln414Lys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is missense (Q414K)
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.596. BayesDel score = 0.0521768.
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 0.070
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_005188.3%3Ac.1240C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-119149232-C-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-119278522-C-A?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-119278522-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005188.3%3Ac.1240…
- OncoKB ↗www.oncokb.org/gene/CBL/Q414K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CBL+c.1240C%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
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 = 0.07). REVEL score = 0.596. BayesDel score = 0.0521768.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CBL, a tumor suppressor and ubiquitin ligase, is inactivated by mutation or deletion in various cancer types including myeloid malignancies.
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.