About CBL
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CBL c.1096-1_1096delinsTT, p.?
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
NM_005188.3:c.1096-1_1096delinsTT disrupts the canonical acceptor splice site (c.1096-1) of CBL intron 7. CBL loss of function is an established disease mechanism for germline RASopathy/Noonan syndrome-like disorders. SpliceAI predicts strong acceptor loss (delta score 0.99), consistent with aberrant splicing and predicted loss of protein function. Under the ClinGen SVI PVS1 framework (PMC6185798), canonical ±1,2 splice variants in genes with an established LoF mechanism are assigned PVS1 at very strong weight.
PM2Moderate
PM2 · moderate
NM_005188.3:c.1096-1_1096delinsTT is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases (allele frequency = 0 in all populations). Under generic ACMG/AMP 2015 rules, PM2 is applied at moderate strength for variants absent from or present at extremely low frequency (<0.1%) in large population cohorts.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
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
0.990 maximum delta
Recorded SpliceAI maximum delta score: 0.990. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 3 not met · 15 not assessed · 8 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.1096-1_1096delinsTT is a canonical splice acceptor site variant in CBL, a gene in which loss of function is a well-established mechanism for Noonan syndrome-like/RASopathy disorders (PVS1 at very strong weight, per ClinGen SVI PVS1 framework PMC6185798).
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele frequency = 0), meeting PM2 at moderate strength (absent from population controls, below 0.1% threshold).
SpliceAI predicts strong disruption of the canonical splice acceptor site (max delta score 0.99, acceptor loss DS_AL=0.99). This splice prediction evidence is captured by PVS1 and is not separately scored as PP3 per PMC6185798 guidance against double-counting.
The variant has not been reported in ClinVar, COSMIC, or in any publication identified through literature search. No functional studies, segregation data, or de novo reports are available. Multiple criteria (PS2, PS3, PS4, PM1, PM6, PP1, PP4) remain unassessed due to lack of evidence.
Under ACMG/AMP 2015 generic combination rules (PMID:25741868), one very strong criterion (PVS1) plus one moderate criterion (PM2) supports classification as Likely Pathogenic.
No criteria match.
Met · 2
PVS1 Very strongNM_005188.3:c.1096-1_1096delinsTT disrupts the canonical acceptor splice site (c.1096-1) of CBL intron 7. CBL loss of function is an established disease mechanism for germline RASopathy/Noonan syndrome-like disorders. SpliceAI predicts strong acceptor loss (delta score 0.99), consistent with aberrant splicing and predicted loss of protein function. Under the ClinGen SVI PVS1 framework (PMC6185798), canonical ±1,2 splice variants in genes with an established LoF mechanism are assigned PVS1 at very strong weight. Details ▾Hide ▴
Evidence considered
- Canonical splice acceptor site affected (c.1096-1
- intron 7/exon 8 boundary)
- CBL loss of function is a confirmed germline disease mechanism (Noonan syndrome-like disorder / RASopathy)
- SpliceAI max delta score 0.99 (DS_AL=0.99
- strong acceptor loss prediction)
- PVS1 gene gate: eligible
- variant bucket: canonical_splice
- ClinGen SVI PVS1 framework (PMC6185798) supports PVS1 at default strength for canonical splice variants
Still missing
- Confirm NM_005188.3 transcript is the clinically relevant transcript for CBL-related disorder
- Confirm that aberrant splicing leads to NMD-competent transcript (exon 8 is not the terminal exon
- NMD predicted)
Sources
PM2 ModerateNM_005188.3:c.1096-1_1096delinsTT is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases (allele frequency = 0 in all populations). Under generic ACMG/AMP 2015 rules, PM2 is applied at moderate strength for variants absent from or present at extremely low frequency (<0.1%) in large population cohorts. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes)
- Absent from gnomAD-Canada v1.0 (HostSeq genomes)
- Allele frequency 0.0 in all populations
- well below PM2 threshold (<0.1%)
Sources
Not met · 3 · evaluated, threshold not reached
BA1 BA1 requires an allele frequency >1% in any general population database (user-specified threshold for non-VCEP assessment). NM_005188.3:c.1096-1_1096delinsTT is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0). Details ▾Hide ▴
Evidence considered
- Allele frequency = 0 in all gnomAD datasets
- far below BA1 threshold (>1%)
Sources
BS1 BS1 requires an allele frequency >0.3% (user-specified threshold for non-VCEP assessment) — greater than expected for the disorder. The variant is absent from all gnomAD population databases (AF=0), falling below the BS1 threshold. Details ▾Hide ▴
Evidence considered
- Allele frequency = 0 in all gnomAD datasets
- below BS1 threshold (>0.3%)
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene product or splicing. SpliceAI predicts a strong deleterious effect on splicing (max delta 0.99, DS_AL=0.99 for acceptor loss), which is contrary to BP4. REVEL and BayesDel are unavailable for this non-SNV variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.99 supports a deleterious splicing effect
- inconsistent with BP4
Sources
Not assessed · 15 · no assessment recorded
PS2 No de novo occurrence data with confirmed maternity and paternity are available for this variant in the case materials. Details ▾Hide ▴
Still missing
- Parental genotyping data needed to assess de novo status
PS3 No well-established in vitro or in vivo functional studies specific to NM_005188.3:c.1096-1_1096delinsTT were identified. The variant is absent from ClinVar, COSMIC, and the literature. Details ▾Hide ▴
Still missing
- Functional studies (e.g.
- RNA splicing assay
- minigene reporter) would be needed to directly assess the impact of this splice variant
PS4 No data on variant prevalence in affected individuals versus controls. The variant is absent from ClinVar and has not been reported in any publication identified in the literature search. Details ▾Hide ▴
Still missing
- Case-level data comparing variant frequency in CBL-related phenotype cohorts versus general population
PM1 The variant affects the intron 7 splice acceptor site. Hotspot analysis did not identify the variant in a known mutational hotspot or critical functional domain. No domain-level data are available for the intronic splice region. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue_significant=false
- exact_variant_listed=no
Still missing
- Domain annotation for exon 8 and flanking intronic regions in CBL protein structure
PM6 No assumed de novo occurrence data (without confirmation of maternity and paternity) are available for this variant. Details ▾Hide ▴
Still missing
- Proband parental genotype data to determine if variant is de novo
PP1 No co-segregation data in multiple affected family members are available for this variant. Details ▾Hide ▴
Still missing
- Family segregation data
PP4 No patient phenotype or family history data specific to a disease with a single genetic etiology are available in the case materials. Details ▾Hide ▴
Still missing
- Patient phenotype description and family history
PP5 The variant is absent from ClinVar; no reputable source has reported this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar (0 submissions)
BS2 No data are available on observation of this variant in healthy adult individuals for a fully penetrant dominant disorder. The variant is absent from all population databases. Details ▾Hide ▴
Still missing
- Healthy adult carrier data for dominant CBL-related disorders
BS3 No well-established in vitro or in vivo functional studies demonstrating no deleterious effect of NM_005188.3:c.1096-1_1096delinsTT were identified. Details ▾Hide ▴
Still missing
- Functional studies showing normal splicing or preserved protein function
BS4 No segregation data in affected family members are available to assess lack of segregation with disease. Details ▾Hide ▴
Still missing
- Family segregation data
BP2 No data are available on observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
- Phasing data with known pathogenic CBL variants
BP5 No data are available on observation of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- Clinical data on alternate molecular diagnoses in carriers
BP6 The variant is absent from ClinVar; no reputable source has reported this variant as benign. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
PS5 No evidence was identified that a different nucleotide change at the same position (c.1096-1 or c.1096) has been established as pathogenic. This variant is absent from ClinVar and the literature. Details ▾Hide ▴
Still missing
- ClinVar data on other variants at the c.1096-1 or c.1096 positions
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 requires comparison of the same amino acid change with a previously established pathogenic variant. This is a canonical splice site variant with no defined amino acid change (protein consequence: p.?); no amino acid-level comparator is available. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame coding deletions/insertions in non-repeat regions and stop-loss variants. NM_005188.3:c.1096-1_1096delinsTT is a canonical splice acceptor site variant, not an in-frame coding indel or stop-loss variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a novel missense change at an amino acid position where a different pathogenic missense change has been established. This is a canonical splice site variant with no defined amino acid residue; classic same-residue PM5 semantics cannot be applied. The automated PM5 candidate harvest also confirmed this (pm5_mode=unknown, eligible_for_classic_pm5_search=false). Details ▾Hide ▴
Evidence considered
- Protein consequence is p.? (unknown)
- no residue coordinate available
- Automated PM5 candidate search: not_applicable
Sources
pm5_candidates
PP2 N/APP2 applies specifically to missense variants in genes where missense variants are a common disease mechanism and benign missense variation is rare. NM_005188.3:c.1096-1_1096delinsTT is a canonical splice site variant, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
PP3 N/AUnder the ClinGen SVI PVS1 recommendations (PMC6185798), PP3 should not be stacked with PVS1 when both rely on the same in silico splice prediction evidence. PVS1 has already been applied for this canonical splice variant based on its predicted disruption of splicing (SpliceAI max delta 0.99). Applying PP3 for the same prediction would constitute double-counting. REVEL and BayesDel scores are unavailable (variant is not an SNV). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.99 (DS_AL=0.99
- DS_DL=0.48) supports deleterious splice effect
- PVS1 already captures this splice prediction evidence
- REVEL/BayesDel not applicable (not an SNV)
Sources
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_005188.3:c.1096-1_1096delinsTT is a canonical splice site variant, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without known function. NM_005188.3:c.1096-1_1096delinsTT is a canonical splice site variant, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the consensus splice site. NM_005188.3:c.1096-1_1096delinsTT is a canonical splice acceptor site variant, not a synonymous variant, and SpliceAI predicts a strong splicing impact. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CBL
- Transcript
- NM_005188.3
- Coding (HGVS c.)
- NM_005188.3:c.1096-1_1096delinsTT
- Protein (HGVS p.)
- NP_005179.2:p.?
- GRCh38
- chr11:119278165 GG>TT
- GRCh37
- chr11:119148875 GG>TT
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
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene product or splicing. SpliceAI predicts a strong deleterious effect on splicing (max delta 0.99, DS_AL=0.99 for acceptor loss), which is contrary to BP4. REVEL and BayesDel are unavailable for this non-SNV variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.99 supports a deleterious splicing effect
- inconsistent with BP4
Sources
PP3 N/AUnder the ClinGen SVI PVS1 recommendations (PMC6185798), PP3 should not be stacked with PVS1 when both rely on the same in silico splice prediction evidence. PVS1 has already been applied for this canonical splice variant based on its predicted disruption of splicing (SpliceAI max delta 0.99). Applying PP3 for the same prediction would constitute double-counting. REVEL and BayesDel scores are unavailable (variant is not an SNV). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.99 (DS_AL=0.99
- DS_DL=0.48) supports deleterious splice effect
- PVS1 already captures this splice prediction evidence
- REVEL/BayesDel not applicable (not an SNV)
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the consensus splice site. NM_005188.3:c.1096-1_1096delinsTT is a canonical splice acceptor site variant, not a synonymous variant, and SpliceAI predicts a strong splicing impact. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99).
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 0.990
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_005188.3%3Ac.1096-1_1096d…
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-119148875-GG-TT?dataset=gn…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-119278165-GG-TT?dataset…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-119278165-GG-TT
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005188.3%3Ac.1096…
- OncoKB ↗www.oncokb.org/gene/CBL/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CBL+c.1096-1_1096delinsTT
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 possible splice impact for this variant (max delta score = 0.99).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).