NM_005188.3:c.1096-1_1096delinsTT

CBL · NP_005179.2:p.? · NM_005188.3

GRCh37: chr11:119148875 GG>TT · GRCh38: chr11:119278165 GG>TT

Gene: CBL Transcript: NM_005188.3

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

CBL

Transcript

NM_005188.3

Protein

NP_005179.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_005188.3:c.1096-1_1096delinsTT is a canonical splice acceptor site variant in CBL, a gene in which loss of function is a well-established mechanism for Noonan syndrome-like/RASopathy disorders (PVS1 at very strong weight, per ClinGen SVI PVS1 framework PMC6185798).

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele frequency = 0), meeting PM2 at moderate strength (absent from population controls, below 0.1% threshold).

SpliceAI predicts strong disruption of the canonical splice acceptor site (max delta score 0.99, acceptor loss DS_AL=0.99). This splice prediction evidence is captured by PVS1 and is not separately scored as PP3 per PMC6185798 guidance against double-counting.

The variant has not been reported in ClinVar, COSMIC, or in any publication identified through literature search. No functional studies, segregation data, or de novo reports are available. Multiple criteria (PS2, PS3, PS4, PM1, PM6, PP1, PP4) remain unassessed due to lack of evidence.

Under ACMG/AMP 2015 generic combination rules (PMID:25741868), one very strong criterion (PVS1) plus one moderate criterion (PM2) supports classification as Likely Pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	NM_005188.3:c.1096-1_1096delinsTT disrupts the canonical acceptor splice site (c.1096-1) of CBL intron 7. CBL loss of function is an established disease mechanism for germline RASopathy/Noonan syndrome-like disorders. SpliceAI predicts strong acceptor loss (delta score 0.99), consistent with aberrant splicing and predicted loss of protein function. Under the ClinGen SVI PVS1 framework (PMC6185798), canonical ±1,2 splice variants in genes with an established LoF mechanism are assigned PVS1 at very strong weight.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment spliceai
PS1	N/A	PS1 requires comparison of the same amino acid change with a previously established pathogenic variant. This is a canonical splice site variant with no defined amino acid change (protein consequence: p.?); no amino acid-level comparator is available.
PS2	Not assessed	No de novo occurrence data with confirmed maternity and paternity are available for this variant in the case materials.
PS3	Not assessed	No well-established in vitro or in vivo functional studies specific to NM_005188.3:c.1096-1_1096delinsTT were identified. The variant is absent from ClinVar, COSMIC, and the literature.
PS4	Not assessed	No data on variant prevalence in affected individuals versus controls. The variant is absent from ClinVar and has not been reported in any publication identified in the literature search.
PS5	Not assessed	No evidence was identified that a different nucleotide change at the same position (c.1096-1 or c.1096) has been established as pathogenic. This variant is absent from ClinVar and the literature.
PM1	Not assessed	The variant affects the intron 7 splice acceptor site. Hotspot analysis did not identify the variant in a known mutational hotspot or critical functional domain. No domain-level data are available for the intronic splice region.
PM2	Met	NM_005188.3:c.1096-1_1096delinsTT is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases (allele frequency = 0 in all populations). Under generic ACMG/AMP 2015 rules, PM2 is applied at moderate strength for variants absent from or present at extremely low frequency (<0.1%) in large population cohorts.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 applies to in-frame coding deletions/insertions in non-repeat regions and stop-loss variants. NM_005188.3:c.1096-1_1096delinsTT is a canonical splice acceptor site variant, not an in-frame coding indel or stop-loss variant.
PM5	N/A	PM5 requires a novel missense change at an amino acid position where a different pathogenic missense change has been established. This is a canonical splice site variant with no defined amino acid residue; classic same-residue PM5 semantics cannot be applied. The automated PM5 candidate harvest also confirmed this (pm5_mode=unknown, eligible_for_classic_pm5_search=false).	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence data (without confirmation of maternity and paternity) are available for this variant.
PP1	Not assessed	No co-segregation data in multiple affected family members are available for this variant.
PP2	N/A	PP2 applies specifically to missense variants in genes where missense variants are a common disease mechanism and benign missense variation is rare. NM_005188.3:c.1096-1_1096delinsTT is a canonical splice site variant, not a missense variant.
PP3	N/A	Under the ClinGen SVI PVS1 recommendations (PMC6185798), PP3 should not be stacked with PVS1 when both rely on the same in silico splice prediction evidence. PVS1 has already been applied for this canonical splice variant based on its predicted disruption of splicing (SpliceAI max delta 0.99). Applying PP3 for the same prediction would constitute double-counting. REVEL and BayesDel scores are unavailable (variant is not an SNV).	pvs1_generic_framework spliceai
PP4	Not assessed	No patient phenotype or family history data specific to a disease with a single genetic etiology are available in the case materials.
PP5	Not assessed	The variant is absent from ClinVar; no reputable source has reported this variant as pathogenic.
BA1	Not met	BA1 requires an allele frequency >1% in any general population database (user-specified threshold for non-VCEP assessment). NM_005188.3:c.1096-1_1096delinsTT is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 requires an allele frequency >0.3% (user-specified threshold for non-VCEP assessment) — greater than expected for the disorder. The variant is absent from all gnomAD population databases (AF=0), falling below the BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available on observation of this variant in healthy adult individuals for a fully penetrant dominant disorder. The variant is absent from all population databases.
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no deleterious effect of NM_005188.3:c.1096-1_1096delinsTT were identified.
BS4	Not assessed	No segregation data in affected family members are available to assess lack of segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_005188.3:c.1096-1_1096delinsTT is a canonical splice site variant, not a missense variant.
BP2	Not assessed	No data are available on observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. NM_005188.3:c.1096-1_1096delinsTT is a canonical splice site variant, not an in-frame indel.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on gene product or splicing. SpliceAI predicts a strong deleterious effect on splicing (max delta 0.99, DS_AL=0.99 for acceptor loss), which is contrary to BP4. REVEL and BayesDel are unavailable for this non-SNV variant.	spliceai
BP5	Not assessed	No data are available on observation of this variant in a case with an alternate molecular basis for disease.
BP6	Not assessed	The variant is absent from ClinVar; no reputable source has reported this variant as benign.
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the consensus splice site. NM_005188.3:c.1096-1_1096delinsTT is a canonical splice acceptor site variant, not a synonymous variant, and SpliceAI predicts a strong splicing impact.

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