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.1 This variant is absent from all large population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at supporting level.2 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.3 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.4 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.5
CBL
Final classification
VUS
PM2BP4
CBL
c.1240C>A
p.Gln414Lys
This variant
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.
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.
Classification rationale
PM2
BP4
VUS
CBL c.1240C>A
PM2 + BP4
→
VUS
Gene diagram
· NM_005188.3 · variants mapped to exon structure
CBL
NM_005188.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes/genomes).Absent from gnomAD-Canada v1.0 (genomes).
✓
BP4
supporting
Benign
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).
BayesDel: 0.052 (predicts benign).SpliceAI max delta: 0.07 (no splicing impactwell below 0.1 threshold).
Assessed · not applied
· 21 not met · 0 not assessed
Pathogenic
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).
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.
PS2
No de novo observation has been reported for this variant in any database or publication.
PS3
No well-established in vitro or in vivo functional studies have been identified for this variant.
PS4
No case-control or prevalence data available.
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.
PM5
No pathogenic missense variant at the same amino acid residue (Q414) was identified in ClinVar.
PM6
No de novo observation (with or without confirmed maternity/paternity) has been reported for this variant.
PP1
No co-segregation data are available for this variant in affected families.
PP2
No HCI prior or gene-specific missense constraint metric is available for CBL to support PP2.
PP3
In silico predictions are mixed and do not reach a consensus of damaging effect.
PP4
No phenotype or clinical data are available for this variant to assess phenotypic specificity.
PP5
No reputable source has reported this variant as pathogenic.
Benign
BA1
Variant is absent from all gnomAD populations; allele frequency is 0% and does not exceed the 1% BA1 threshold.
BS1
Variant is absent from all gnomAD populations; allele frequency is 0% and does not exceed the 0.3% BS1 threshold.
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.
BS3
No well-established functional studies demonstrating a neutral or non-damaging effect have been identified for this variant.
BS4
No segregation data in affected families are available to assess lack of co-segregation with disease.
BP2
No evidence that this variant has been observed in trans with a known pathogenic CBL variant.
BP5
No case has been identified in which this variant is present alongside an alternative molecular basis for disease.
BP6
No reputable source has classified this variant as benign.
N/A · 2
BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
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.
COSMIC
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.
Sources & reference links