Analysis in progress
Initialising…
0%
complete
This report is still being assembled — sections appear as each stage finishes. It isn't final yet.
CBL
Final classification
VUS
CBL c.1147A>G · p.Ile383Val
CBL

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.

Gene
CBL
Transcript
NM_005188.3
HGVS · transcript:coding
NM_005188.3:c.1147A>G
Consequence
N/A
GRCh38
chr11:119278217 A>G
GRCh37
chr11:119148927 A>G
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 moderate; combination = 1 moderate, 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 moderate; combination = 1 moderate, which maps to VUS.
Classification rationale
PM2 VUS
CBL c.1147A>G

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.1 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 v1.0.2 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 0.01.3

PM2 → VUS
1 clinvar ↗
2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
3 revelbayesdelspliceai ↗
Gene diagram · NM_005188.3 · variants mapped to exon structure
CBL NM_005188.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 20 assessed
Applied · 1
Strength Supporting Moderate Strong Very strong
✓
PM2 moderate Pathogenic
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.
gnomAD v2.1 total AF 3.97943428362224e-06gnomAD v4.1 total AF 1.8610999100468377e-06absent from gnomAD-Canada v1.0.
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied
Pathogenic
PS1 No evidence was identified showing that this nucleotide change creates the same amino acid substitution as an established pathogenic variant.
PS2 No confirmed de novo occurrence with verified parental relationships was identified.
PS3 No variant-specific well-established functional study demonstrating a damaging effect was identified.
PS4 No case-control enrichment or multiple affected observations sufficient to show increased prevalence in affected individuals versus controls were identified.
PM1 Available hotspot review does not support location in a well-established functional domain or statistically significant mutational hotspot for this criterion.
PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context.
PM6 No assumed de novo occurrence data were identified.
PP1 No segregation data were identified.
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.
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.
PP4 No phenotype or family history data were identified that are highly specific for a CBL-related disorder.
Benign
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.
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.
BS2 No evidence was identified showing this variant in healthy adult individuals in numbers sufficient for BS2.
BS3 No well-established functional study demonstrating a benign effect was identified.
BS4 No data were identified showing lack of segregation with disease in affected family members.
BP1 Available evidence does not support use of BP1 for this gene and variant type.
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.
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.
BP5 No alternate molecular basis for the observed phenotype was identified.
N/A · 7 PVS1 · PM4 · PM5 · PP5 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
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.
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).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019% · 3 / 1,611,950
0 hom · FAF 0.00055%
Admixed American
2 / 59,988
0.0033%
European (non-Finnish)
1 / 1,178,132
8.5e-05%
+ 8 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004% · 1 / 251,292
0 hom
Admixed American
1 / 34,588
0.0029%
+ 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 4804130)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.605. BayesDel score = 0.0719745.
SpliceAI ↗
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. CBL, a tumor suppressor and ubiquitin ligase, is inactivated by mutation or deletion in various cancer types including myeloid malignancies.
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 1 PMID not cited in assessment
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR