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.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.CBL encodes a protein that helps attach ubiquitin to activated signaling proteins, marking them for breakdown and helping limit signals from receptors such as EGFR, PDGFR, MET, and FLT3. Germline changes in CBL are associated with Noonan syndrome and an increased predisposition to juvenile myelomonocytic leukemia. CBL is involved in cancer development, with alterations reported in blood cancers, lung adenocarcinoma, and melanoma.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at supporting strength: gnomAD v4.1 total AF 6.19554e-07 and maximum subpopulation AF 1.5998e-05 are below 0.0001.
No benign criterion marked as applied in the recorded assessment.
VUS: PM2 at supporting strength alone does not satisfy any generic ACMG/AMP combination threshold.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 1 / 1,614,064 alleles. Recorded AF 6.19554e-07. Recorded homozygote count 0.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.628. Refer to the recorded PP3/BP4 rationale for interpretation.
1 Uncertain significance.
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.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 4 not met · 19 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No criterion in this segregation/de novo group can be assessed because the available evidence contains no variant-specific proband, parental, familial segregation, or non-segregation observations.
No governing CBL VCEP or gene-specific framework was available; generic ACMG/AMP population rules were used.
The population evidence supports PM2 at supporting strength, while BA1 and BS1 are not met because observed frequencies are far below their thresholds; BS2 is not assessable because no healthy adult homozygous or hemizygous observation is documented.
No criteria match.
PM2 is met at supporting strength. No governing CBL VCEP or gene-specific population-source requirement was available, so the generic SVI recommendation of AF <=0.0001 applies. The variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1, with total AF 6.19554e-07 and highest observed subpopulation AF 1.5998e-05; homozygotes are absent. Both reported frequencies are below 0.0001.
Generic ClinGen SVI PM2: allele frequency <=0.0001, applied at supporting strength; no VCEP-specific rule available.
PP3 applies to this missense variant through the REVEL path only. The variant is NM_005188.3:c.1238G>A (p.Gly413Asp), and its REVEL score is 0.628. This is below the generic ClinGen SVI REVEL supporting threshold of >=0.644 from Pejaver et al. 2022 (PMID:36413997), so PP3 is not met at any calibrated strength. The available SpliceAI score is not used because splice predictions do not provide PP3 support for a missense consequence, and BayesDel has no generic ACMG strength calibration.
missense_requires_revel; generic_revel_pp3_supporting_threshold >=0.644
BA1 is not met. Under the generic ACMG/AMP fallback, BA1 requires an allele frequency of at least 0.05 (ACMG/AMP 2015, PMID:25741868). The variant is absent from gnomAD v2.1 and has a gnomAD v4.1 all-comers total allele frequency of 6.19554e-07 (1/1,614,064 alleles), with the highest reported subpopulation frequency 1.5998e-05 (1/62,508 alleles), both far below 0.05. No governing CBL VCEP specification or non-cancer/exome-only override was available.
Generic ACMG/AMP BA1: allele frequency >=0.05; no VCEP-specific rule available.
BS1 is not met. Under the generic ACMG/AMP fallback, BS1 requires an allele frequency greater than or equal to 0.01; the variant is absent from gnomAD v2.1 and has a gnomAD v4.1 total allele frequency of 6.19554e-07, with a highest observed subpopulation frequency of 1.5998e-05. These frequencies are far below 0.01. No governing CBL VCEP specification or non-cancer/exome-only override was available.
Generic ACMG/AMP BS1: allele frequency >=0.01; no VCEP-specific rule available.
BP4 applies to this missense variant through the REVEL path only. The variant is NM_005188.3:c.1238G>A (p.Gly413Asp), and its REVEL score is 0.628. This is above the generic ClinGen SVI REVEL supporting threshold of <=0.29 from Pejaver et al. 2022 (PMID:36413997), so BP4 is not met. The SpliceAI score is not substituted because a missense variant must be adjudicated with REVEL for PP3/BP4, and BayesDel has no generic ACMG strength calibration.
missense_requires_revel; generic_revel_bp4_supporting_threshold <=0.29
PS1 cannot be assessed because no independent pathogenic or likely pathogenic variant producing the same amino-acid substitution p.Gly413Asp was identified in the available case evidence. The single ClinVar record is the target variant itself and is classified as uncertain significance by one submitter; it does not provide a same-amino-acid comparator.
Generic PS1 requires a previously established pathogenic variant causing the same amino-acid change; no governing CBL-specific specification was available.
PS2 cannot be assessed because the available case evidence does not document a confirmed de novo occurrence in the proband, including verified parental genotypes, maternity/paternity, or testing details. The variant is a missense change in CBL (NM_005188.3:c.1238G>A; p.Gly413Asp), but variant consequence and population observations do not establish de novo status.
No validated variant-specific functional assay was identified for NM_005188.3:c.1238G>A (NP_005179.2:p.Gly413Asp). The available ClinVar record is a single-submitter uncertain-significance record without functional results, and OncoKB reports no variant-specific reviewed functional evidence. Therefore PS3 cannot be assessed; no assay controls, biological readout, or calibrated functional effect is available to support this criterion.
PS4 requires case-control enrichment or a sufficiently documented excess of the exact variant in affected individuals relative to appropriate controls. The available case evidence contains no case-control counts, odds ratio, likelihood ratio, or qualifying enrichment study for NM_005188.3:c.1238G>A (NP_005179.2:p.Gly413Asp), so PS4 cannot be assessed.
PS4 requires qualifying case-control enrichment or equivalent exact-variant affected-case excess; no such dataset is available.
PM1 cannot be assessed because no governing CBL-specific framework or authoritative domain table was available, and the case evidence provides no validated critical functional-domain boundary containing residue 413. The cancer-hotspot query found no statistically significant hotspot for CBL G413, but absence of a hotspot does not establish whether residue 413 lies in another approved critical domain.
Generic PM1 requires a well-established critical functional domain, mutational hotspot, or other critical region; a CBL-specific specification would take precedence but was not available.
No applicable CBL-specific VCEP specification was available, so generic ACMG/AMP PM3 was considered. The available case evidence does not report an affected proband carrying NM_005188.3:c.1238G>A in trans with a pathogenic or likely pathogenic CBL variant, nor does it provide phase, biallelic disease, or informative parental testing. The variant is therefore not assessable for PM3 from the available evidence.
PM5 cannot be assessed because no other missense variant at CBL residue 413 with an established pathogenic or likely pathogenic classification was identified. The case's comparator-candidate artifact contains zero same-residue candidates and explicitly does not establish classic PM5 semantics; the target ClinVar record is not an eligible comparator.
Generic PM5 requires an established pathogenic or likely pathogenic missense variant at the same residue; no governing CBL-specific specification was available.
PM6 cannot be assessed because there is no documented report that this variant was assumed to be de novo without parental confirmation. No proband report, parental testing status, family history, or source-level case observation is available to support an unconfirmed de novo inference.
PP1 cannot be assessed because no affected relatives, familial cases, genotype-positive relatives, or informative meioses are documented for NM_005188.3:c.1238G>A. There is therefore no segregation series from which to judge consistency with disease status or assign supporting, moderate, or strong strength.
PP2 cannot be assessed because the available evidence does not establish that CBL is a gene in which missense variants are a predominant disease mechanism while benign missense variation is limited. The gene-level context supports CBL loss of function as a germline disease mechanism, but that does not by itself satisfy PP2's missense-specific requirement.
Generic PP2 requires a gene with a high proportion of pathogenic missense variants and low benign missense variation; no governing CBL-specific specification was available.
PP4 requires a highly specific phenotype or family history consistent with the associated disease. No patient phenotype, diagnostic features, family history, or disease-specific clinical description was provided for the variant case, so phenotype specificity cannot be evaluated.
PP4 requires a specific phenotype or family history consistent with the relevant disease; clinical phenotype data are absent.
PP5 is restricted here to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification. ClinVar variation 1412642 is an exact match, but its only submission is a single-laboratory Uncertain significance assertion with zero expert-panel submissions; therefore PP5 is not triggered, and no qualifying expert-panel assertion is available to assess.
PP5 applies only to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary laboratory and aggregate assertions do not qualify.
BS2 cannot be applied from the available population data. gnomAD v4.1 reports zero homozygotes, and gnomAD v2.1 reports the variant as absent, but BS2 requires observation of the variant in healthy adult individuals in the homozygous or hemizygous state. The available gnomAD records do not establish healthy-adult phenotype or ascertainment status for a homozygous or hemizygous carrier.
Generic ACMG/AMP BS2 requires observation in healthy adults in the homozygous or hemizygous state.
No validated variant-specific functional assay was identified that demonstrates preserved CBL function for NM_005188.3:c.1238G>A (NP_005179.2:p.Gly413Asp). The available ClinVar record is a single-submitter uncertain-significance record without functional results, and OncoKB reports no variant-specific reviewed functional evidence. Absence of an assay cannot establish BS3, so this criterion remains unassessed.
BS4 cannot be assessed because the case evidence does not document unaffected relatives who were tested and found to carry the variant in a phenotype-relevant family. The available population frequency and predictor data do not constitute non-segregation evidence.
BP1 cannot be assessed because the available evidence does not establish that CBL-related disease is caused predominantly by truncating or other loss-of-function variants with missense variants rarely involved in disease. Although the gene-level context supports loss of function, it does not establish the rarity of pathogenic missense variation required for BP1.
Generic BP1 requires a gene in which pathogenic missense variants are known to be uncommon because the disease mechanism is predominantly truncating or loss of function; no governing CBL-specific specification was available.
No applicable CBL-specific VCEP specification was available, so generic ACMG/AMP BP2 was considered. The available case evidence does not document this variant in trans with a pathogenic or likely pathogenic variant in an affected individual, or in cis with a pathogenic variant in a recessive disease context. Phase, co-occurrence, and informative inheritance observations are absent; therefore BP2 cannot be assessed.
BP5 requires the variant to be found in an affected individual with a different molecular explanation for the phenotype, or another qualifying alternative molecular etiology under the governing framework. No such affected-individual molecular finding or alternative diagnosis is documented for this variant, so BP5 cannot be assessed.
BP5 requires a qualifying alternative molecular etiology in an affected individual; no such evidence is available.
BP6 is restricted here to an exact-variant ClinVar expert-panel Benign or Likely benign classification. ClinVar variation 1412642 is an exact match, but its only submission is a single-laboratory Uncertain significance assertion with zero expert-panel submissions; therefore BP6 is not triggered, and no qualifying expert-panel assertion is available to assess.
BP6 applies only to an exact-variant ClinVar expert-panel Benign or Likely benign classification; ordinary laboratory and aggregate assertions do not qualify.
deterministic_prefilter: requires_null_variant_class
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
deterministic_prefilter: requires_repeat_region_indel
deterministic_prefilter: requires_synonymous
Every interpreted variant in CBL, mapped onto the exon structure of NM_005188.3. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Remaining individuals1 / 62,508 | 1.6e-05 |
This variant is present in gnomAD v4.1 (AF= 6.19554e-07; MAF= 0.00006%, 1/1614064 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.5998e-05; MAF= 0.00160%, 1/62508 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
PP3 applies to this missense variant through the REVEL path only. The variant is NM_005188.3:c.1238G>A (p.Gly413Asp), and its REVEL score is 0.628. This is below the generic ClinGen SVI REVEL supporting threshold of >=0.644 from Pejaver et al. 2022 (PMID:36413997), so PP3 is not met at any calibrated strength. The available SpliceAI score is not used because splice predictions do not provide PP3 support for a missense consequence, and BayesDel has no generic ACMG strength calibration.
missense_requires_revel; generic_revel_pp3_supporting_threshold >=0.644
BP4 applies to this missense variant through the REVEL path only. The variant is NM_005188.3:c.1238G>A (p.Gly413Asp), and its REVEL score is 0.628. This is above the generic ClinGen SVI REVEL supporting threshold of <=0.29 from Pejaver et al. 2022 (PMID:36413997), so BP4 is not met. The SpliceAI score is not substituted because a missense variant must be adjudicated with REVEL for PP3/BP4, and BayesDel has no generic ACMG strength calibration.
missense_requires_revel; generic_revel_bp4_supporting_threshold <=0.29
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16). REVEL score = 0.628. BayesDel score = 0.171278.
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.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 6.19554e-07; MAF= 0.00006%, 1/1614064 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.5998e-05; MAF= 0.00160%, 1/62508 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1412642)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16). REVEL score = 0.628. BayesDel score = 0.171278.
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.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.