NM_005188.3:c.1240C>A

CBL · NP_005179.2:p.(Gln414Lys) · NM_005188.3

GRCh37: chr11:119149232 C>A · GRCh38: chr11:119278522 C>A

Gene: CBL Transcript: NM_005188.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

CBL

Transcript

NM_005188.3

Protein

NP_005179.2:p.(Gln414Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

This variant is absent from all large population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at supporting level.

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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). The variant-level assessment confirms bucket='other' and apply_generic_pvs1_framework=false.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No pathogenic variant with the same amino acid change (Q414K) arising from a different nucleotide substitution has been identified in ClinVar or the literature. Without a comparator, PS1 cannot be applied.	clinvar
PS2	Not met	No de novo observation has been reported for this variant in any database or publication.	clinvar
PS3	Not met	No well-established in vitro or in vivo functional studies have been identified for this variant. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence.	oncokb
PS4	Not met	No case-control or prevalence data available. The variant is absent from ClinVar and has not been reported in affected individuals.	clinvar gnomad_v2 gnomad_v4
PS5	Not met	No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar entirely.	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Q414) was identified in ClinVar. The PM5 candidate search returned zero same-residue comparators.	pm5_candidates clinvar
PM6	Not met	No de novo observation (with or without confirmed maternity/paternity) has been reported for this variant.	clinvar
PP1	Not met	No co-segregation data are available for this variant in affected families.
PP2	Not met	No HCI prior or gene-specific missense constraint metric is available for CBL to support PP2. The HCI prior lookup returned 'gene_not_supported'.
PP3	Not met	In silico predictions are mixed and do not reach a consensus of damaging effect. REVEL score is 0.596 (modestly elevated but below conventional PP3 thresholds of 0.7–0.75), while BayesDel score is 0.052 (predicts benign) and SpliceAI max delta is 0.07 (no splice impact).	revel bayesdel spliceai
PP4	Not met	No phenotype or clinical data are available for this variant to assess phenotypic specificity.
PP5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	Variant is absent from all gnomAD populations; allele frequency is 0% and does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from all gnomAD populations; allele frequency is 0% and does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating a neutral or non-damaging effect have been identified for this variant.	oncokb
BS4	Not met	No segregation data in affected families are available to assess lack of co-segregation with disease.
BP1	N/A	CBL is not a gene where only truncating variants cause disease; pathogenic missense variants in CBL are well-established in RASopathies and myeloid malignancies.	pvs1_gene_context
BP2	Not met	No evidence that this variant has been observed in trans with a known pathogenic CBL variant.
BP4	Met	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 spliceai
BP5	Not met	No case has been identified in which this variant is present alongside an alternative molecular basis for disease.
BP6	Not met	No reputable source has classified this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	NM_005188.3:c.1240C>A is a missense variant (p.Gln414Lys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.