Variant classification summary

NM_005188.3:c.1238G>A

CBL · NP_005179.2:p.(Gly413Asp) · NM_005188.3

GRCh37: chr11:119149230 G>A · GRCh38: chr11:119278520 G>A

Gene: CBL Transcript: NM_005188.3

Final call

VUS

PM2 supporting

Variant details

Gene

CBL

Transcript

NM_005188.3

Protein

NP_005179.2:p.(Gly413Asp)

gnomAD AF

6.195541192914283e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 frequencies are below the 0.0001 threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting criterion alone does not meet any pathogenic, likely pathogenic, benign, or likely benign combination threshold, so the call is VUS.

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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_005188.3:c.1238G>A in CBL is a missense substitution predicted to produce NP_005179.2:p.(Gly413Asp). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no validated pathogenic same-amino-acid comparator for p.Gly413Asp was identified.	clinvar
PS2	Not assessed	Not assessed: no confirmed de novo result or verified parental genotypes are documented for the proband's CBL p.Gly413Asp variant.
PS3	Not assessed	Not assessed: no variant-specific validated functional assay, controls, or biological readout were available for p.Gly413Asp.	clinvar oncokb
PS4	Not assessed	Not assessed: no case-control counts or enrichment statistic for NM_005188.3:c.1238G>A were available.
PM1	Not assessed	Not assessed: no authoritative CBL domain boundary was available for residue 413, and no significant CBL G413 hotspot was found.
PM2	Met	Met at supporting strength: gnomAD v4.1 total AF 6.19554e-07 and maximum subpopulation AF 1.5998e-05 are below 0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation or phased pathogenic CBL variant in trans is documented for NM_005188.3:c.1238G>A.
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_005188.3:c.1238G>A in CBL is a missense substitution predicted to produce NP_005179.2:p.(Gly413Asp). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: zero eligible pathogenic or likely pathogenic same-residue comparator variants were identified at CBL residue 413.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no published or case-level evidence describes this CBL variant as de novo without parental confirmation.
PP1	Not assessed	Not assessed: zero affected relatives or informative meioses are documented for segregation of CBL c.1238G>A.
PP2	Not assessed	Not assessed: CBL loss-of-function evidence does not establish the missense-predominant disease mechanism and low benign missense variation required for PP2.	pvs1_gene_context
PP3	Not met	Not met: REVEL 0.628 is below the >=0.644 supporting PP3 threshold from the ClinGen SVI calibration.	revel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no patient phenotype, family history, or disease-specific clinical description was available.
PP5	Not assessed	Not assessed: ClinVar has one exact-match laboratory Uncertain significance submission and zero expert-panel Pathogenic or Likely pathogenic assertions.	clinvar
BA1	Not met	Not met: gnomAD v4.1 maximum observed population AF is 1.5998e-05, far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 maximum observed population AF is 1.5998e-05, far below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes, but no healthy adult homozygous or hemizygous observation is documented for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated assay demonstrated preserved CBL function for p.Gly413Asp with appropriate controls and a benign calibration.	clinvar oncokb
BS4	Not assessed	Not assessed: no tested unaffected relatives carrying CBL c.1238G>A are documented to demonstrate non-segregation.
BP1	Not assessed	Not assessed: CBL loss-of-function evidence does not establish that pathogenic missense variants are rare enough to satisfy BP1.	pvs1_gene_context
BP2	Not assessed	Not assessed: no phased cis or trans co-occurrence with a pathogenic variant is documented for NM_005188.3:c.1238G>A.
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_005188.3:c.1238G>A in CBL is a missense substitution predicted to produce NP_005179.2:p.(Gly413Asp). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.628 exceeds the <=0.29 supporting BP4 threshold from the ClinGen SVI calibration.	revel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no affected individual with an alternative molecular explanation or qualifying alternative diagnosis was documented.
BP6	Not assessed	Not assessed: ClinVar has one exact-match laboratory Uncertain significance submission and zero expert-panel Benign or Likely benign assertions.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_005188.3:c.1238G>A in CBL is a missense substitution predicted to produce NP_005179.2:p.(Gly413Asp). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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