NM_005188.3:c.1147A>G

CBL · NP_005179.2:p.(Ile383Val) · NM_005188.3

GRCh37: chr11:119148927 A>G · GRCh38: chr11:119278217 A>G

Gene: CBL Transcript: NM_005188.3

Final call

VUS

PM2 moderate

Variant details

Gene

CBL

Transcript

NM_005188.3

Protein

NP_005179.2:p.(Ile383Val)

gnomAD AF

1.8610999100468377e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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	N/A	This is a missense variant, and the generic PVS1 framework does not apply because it is not a nonsense, frameshift, or canonical ±1/2 splice-site variant.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that this nucleotide change creates the same amino acid substitution as an established pathogenic variant.
PS2	Not assessed	No confirmed de novo occurrence with verified parental relationships was identified.
PS3	Not assessed	No variant-specific well-established functional study demonstrating a damaging effect was identified.	oncokb
PS4	Not assessed	No case-control enrichment or multiple affected observations sufficient to show increased prevalence in affected individuals versus controls were identified.	clinvar
PM1	Not met	Available hotspot review does not support location in a well-established functional domain or statistically significant mutational hotspot for this criterion.	hotspots
PM2	Met	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 gnomad_v4 gnomad_canada
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context.
PM4	N/A	This is a missense substitution and does not cause a protein length change from an in-frame insertion/deletion or stop-loss event.
PM5	N/A	Classic same-residue PM5 use could not be confirmed safely for this gene/framework, and no qualifying pathogenic same-residue comparator was established.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence data were identified.
PP1	Not assessed	No segregation data were identified.
PP2	Not assessed	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	Not assessed	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.	revel bayesdel spliceai
PP4	Not assessed	No phenotype or family history data were identified that are highly specific for a CBL-related disorder.
PP5	N/A	No reputable source classified this variant as pathogenic or likely pathogenic in a manner suitable for PP5, and the available ClinVar record is uncertain significance.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in numbers sufficient for BS2.
BS3	Not assessed	No well-established functional study demonstrating a benign effect was identified.	oncokb
BS4	Not assessed	No data were identified showing lack of segregation with disease in affected family members.
BP1	Not assessed	Available evidence does not support use of BP1 for this gene and variant type.
BP2	Not assessed	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.
BP3	N/A	This criterion is not applicable because the variant is not an in-frame deletion or insertion in a repetitive region.
BP4	Not assessed	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.	revel bayesdel spliceai
BP5	Not assessed	No alternate molecular basis for the observed phenotype was identified.
BP6	N/A	No reputable source classified this variant as benign or likely benign in a manner suitable for BP6, and the available ClinVar record is uncertain significance.	clinvar
BP7	N/A	This criterion is not applicable because the variant is missense rather than synonymous or intronic at a nonconserved splice position.	spliceai

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