About CBL
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CBL c.1147A>G, p.(Ile383Val)
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: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
This variant is very rare in population databases, with AF 0.00040% in gnomAD v2.1 (1/251292 alleles) and AF 0.00019% in gnomAD v4.1 (3/1611950 alleles), both below the 0.1% PM2 threshold, and it is absent from gnomAD-Canada v1.0.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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 moderate; combination = 1 moderate, 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
3 / 1,611,950 alleles
gnomAD v4.1: 3 / 1,611,950 alleles. Recorded AF 1.8611e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97943e-06; MAF= 0.00040%, 1/251292 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89118e-05; MAF= 0.00289%, 1/34588 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance.
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.
28 criteria with recorded statuses: 1 met · 3 not met · 17 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The CBL NM_005188.3:c.1147A>G (p.Ile383Val, p.I383V) variant has been reported in ClinVar as uncertain significance with two clinical laboratory submissions.
This variant is very rare in population databases, observed at 1/251292 alleles in gnomAD v2.1 and 3/1611950 alleles in gnomAD v4.1, and it was not observed in gnomAD-Canada v1.0.
Available computational evidence is not sufficient for a directional computational criterion: REVEL is 0.605 and BayesDel is 0.0719745, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01.
No criteria match.
Met · 1
PM2 ModerateThis variant is very rare in population databases, with AF 0.00040% in gnomAD v2.1 (1/251292 alleles) and AF 0.00019% in gnomAD v4.1 (3/1611950 alleles), both below the 0.1% PM2 threshold, and it is absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- gnomAD v2.1 total AF 3.97943428362224e-06
- gnomAD v4.1 total AF 1.8610999100468377e-06
- absent from gnomAD-Canada v1.0.
Sources
Not met · 3 · evaluated, threshold not reached
PM1 Available hotspot review does not support location in a well-established functional domain or statistically significant mutational hotspot for this criterion. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- Cancer Hotspots review reported no hotspot row for CBL I383 and stated that the variant does not lie in a statistically significant hotspot.
Sources
BA1 Population frequency does not meet the benign stand-alone threshold: the highest observed population frequency is 0.00333% in gnomAD v4.1 Admixed American, which is well below the 1% BA1 threshold. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- Highest observed subpopulation AF was 3.3340001333600056e-05 in gnomAD v4.1 AMR.
Sources
BS1 Population frequency does not support BS1: the highest observed population frequency is 0.00333% in gnomAD v4.1 Admixed American, which is below the 0.3% BS1 threshold. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- Highest observed subpopulation AF was 3.3340001333600056e-05 in gnomAD v4.1 AMR.
Sources
Not assessed · 17 · no assessment recorded
PS1 No evidence was identified showing that this nucleotide change creates the same amino acid substitution as an established pathogenic variant. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- No qualifying PS1 comparator was found in the reviewed sources.
Still missing
- Same-amino-acid pathogenic comparator evidence was not identified.
PS2 No confirmed de novo occurrence with verified parental relationships was identified. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- No de novo evidence was present in the reviewed sources.
Still missing
- De novo case data were not available.
PS3 No variant-specific well-established functional study demonstrating a damaging effect was identified. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- OncoKB did not identify reviewed variant-specific functional evidence for this variant.
Still missing
- Variant-specific functional assay data were not identified.
Sources
PS4 No case-control enrichment or multiple affected observations sufficient to show increased prevalence in affected individuals versus controls were identified. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- ClinVar contains two clinical laboratory submissions classifying the variant as uncertain significance
- without evidence of statistical enrichment.
Still missing
- Affected-case enrichment data were not available.
Sources
PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- No PM3-relevant observations were identified.
Still missing
- Phase and recessive-case data were not available.
PM6 No assumed de novo occurrence data were identified. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- No PM6-relevant observations were identified.
Still missing
- Assumed de novo case data were not available.
PP1 No segregation data were identified. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- No PP1-relevant family data were identified.
Still missing
- Family segregation evidence was not available.
PP2 Available evidence does not establish that missense variation in CBL is the predominant disease mechanism with low rates of benign missense variation for this criterion. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- No PP2-specific gene-level evidence was provided.
Still missing
- Gene-level missense constraint/mechanism evidence specific to PP2 was not identified.
PP3 Computational evidence is limited and not sufficiently directional for PP3: REVEL is 0.605 and BayesDel is 0.0719745, while SpliceAI predicts no meaningful splice impact with a max delta score of 0.01. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- REVEL 0.605
- BayesDel 0.0719745
- SpliceAI max delta 0.01.
Still missing
- No gene-specific computational threshold framework was available.
Sources
PP4 No phenotype or family history data were identified that are highly specific for a CBL-related disorder. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- No PP4-relevant phenotype evidence was identified.
Still missing
- Phenotype specificity data were not available.
BS2 No evidence was identified showing this variant in healthy adult individuals in numbers sufficient for BS2. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- No BS2-relevant observation set was identified.
Still missing
- Healthy adult observation data were not available.
BS3 No well-established functional study demonstrating a benign effect was identified. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- OncoKB did not identify reviewed variant-specific functional evidence for this variant.
Still missing
- Variant-specific benign functional assay data were not identified.
Sources
BS4 No data were identified showing lack of segregation with disease in affected family members. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- No BS4-relevant family data were identified.
Still missing
- Non-segregation family data were not available.
BP1 Available evidence does not support use of BP1 for this gene and variant type. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- No BP1-specific gene-mechanism evidence was provided.
Still missing
- Gene-level evidence required for BP1 was not identified.
BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- No BP2-relevant phase observations were identified.
Still missing
- Phase information was not available.
BP4 Computational evidence does not support a benign interpretation: REVEL is 0.605 and BayesDel is 0.0719745, while SpliceAI shows no significant splice effect with a max delta score of 0.01; this is insufficient to apply BP4. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- REVEL 0.605
- BayesDel 0.0719745
- SpliceAI max delta 0.01.
Still missing
- No gene-specific benign computational threshold framework was available.
Sources
BP5 No alternate molecular basis for the observed phenotype was identified. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- No BP5-relevant evidence was identified.
Still missing
- Clinical correlation and alternate-cause data were not available.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the generic PVS1 framework does not apply because it is not a nonsense, frameshift, or canonical ±1/2 splice-site variant. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- CBL loss-of-function is an established germline disease mechanism
- but NM_005188.3:c.1147A>G is not in a generic null-variant PVS1 category.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗PMID:25952305 ↗PMID:40568716 ↗PMID:41062690 ↗PMID:24451042 ↗PMID:26467218 ↗
PM4 N/AThis is a missense substitution and does not cause a protein length change from an in-frame insertion/deletion or stop-loss event. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- Protein consequence is p.(Ile383Val)
- a single amino acid substitution.
PM5 N/AClassic same-residue PM5 use could not be confirmed safely for this gene/framework, and no qualifying pathogenic same-residue comparator was established. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- PM5 candidate review marked classic PM5 semantics as unconfirmed and found no comparator candidates.
Still missing
- A framework-confirmed same-residue pathogenic comparator was not identified.
Sources
pm5_candidates
PP5 N/ANo reputable source classified this variant as pathogenic or likely pathogenic in a manner suitable for PP5, and the available ClinVar record is uncertain significance. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- ClinVar lists the variant as uncertain significance with two clinical laboratory submissions and no expert panel review.
Sources
BP3 N/AThis criterion is not applicable because the variant is not an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- Protein consequence is a missense substitution
- not an in-frame indel.
BP6 N/ANo reputable source classified this variant as benign or likely benign in a manner suitable for BP6, and the available ClinVar record is uncertain significance. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- ClinVar lists the variant as uncertain significance with no benign or likely benign expert assertion.
Sources
BP7 N/AThis criterion is not applicable because the variant is missense rather than synonymous or intronic at a nonconserved splice position. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- Protein consequence is p.(Ile383Val)
- SpliceAI shows no meaningful splice effect but BP7 is restricted to synonymous/intronic contexts.
Sources
Identifiers
- Gene
- CBL
- Transcript
- NM_005188.3
- Coding (HGVS c.)
- NM_005188.3:c.1147A>G
- Protein (HGVS p.)
- NP_005179.2:p.(Ile383Val)
- GRCh38
- chr11:119278217 A>G
- GRCh37
- chr11:119148927 A>G
- ClinVar
- 4804130
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
3 / 1,611,950 alleles
AF 1.86e-06 · 0 homozygotes · FAF 5.53e-06
gnomAD v2.1
1 / 251,292 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,611,950 alleles · 0 hom · FAF 5.5e-06
| Admixed American2 / 59,988 | 3.3e-05 |
| European (non-Finnish)1 / 1,178,132 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 251,292 alleles · 0 hom
| Admixed American1 / 34,588 | 2.9e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.8611e-06; MAF= 0.00019%, 3/1611950 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.334e-05; MAF= 0.00333%, 2/59988 alleles, homozygotes = 0); grpmax FAF= 5.53e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97943e-06; MAF= 0.00040%, 1/251292 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89118e-05; MAF= 0.00289%, 1/34588 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.605
- BayesDel
- 0.072
How the predictions were used
PP3 Computational evidence is limited and not sufficiently directional for PP3: REVEL is 0.605 and BayesDel is 0.0719745, while SpliceAI predicts no meaningful splice impact with a max delta score of 0.01. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- REVEL 0.605
- BayesDel 0.0719745
- SpliceAI max delta 0.01.
Still missing
- No gene-specific computational threshold framework was available.
Sources
BP4 Computational evidence does not support a benign interpretation: REVEL is 0.605 and BayesDel is 0.0719745, while SpliceAI shows no significant splice effect with a max delta score of 0.01; this is insufficient to apply BP4. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- REVEL 0.605
- BayesDel 0.0719745
- SpliceAI max delta 0.01.
Still missing
- No gene-specific benign computational threshold framework was available.
Sources
BP7 N/AThis criterion is not applicable because the variant is missense rather than synonymous or intronic at a nonconserved splice position. Details ▾Hide ▴
Rule
generic_acmg
Evidence considered
- Protein consequence is p.(Ile383Val)
- SpliceAI shows no meaningful splice effect but BP7 is restricted to synonymous/intronic contexts.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.605. BayesDel score = 0.0719745.
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3 / 1,611,950 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
2 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/4804130/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-119148927-A-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-119278217-A-G?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-119278217-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005188.3%3Ac.1147…
- OncoKB ↗www.oncokb.org/gene/CBL/I383V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CBL+c.1147A%3EG
- 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= 1.8611e-06; MAF= 0.00019%, 3/1611950 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.334e-05; MAF= 0.00333%, 2/59988 alleles, homozygotes = 0); grpmax FAF= 5.53e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97943e-06; MAF= 0.00040%, 1/251292 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89118e-05; MAF= 0.00289%, 1/34588 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 4804130)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.605. BayesDel score = 0.0719745.
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.