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).1 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).2 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.3 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.4 Under ACMG/AMP 2015 generic combination rules (PMID:25741868), one very strong criterion (PVS1) plus one moderate criterion (PM2) supports classification as Likely Pathogenic.5
CBL
Final classification
Likely Pathogenic
CBL c.1096-1_1096delinsTT · p.?
CBL
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).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
CBL c.1096-1_1096delinsTT
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
5
generic_acmg_combination_rules
Gene diagram
· NM_005188.3 · variants mapped to exon structure
CBL
NM_005188.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
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.
Canonical splice acceptor site affected (c.1096-1intron 7/exon 8 boundary)CBL loss of function is a confirmed germline disease mechanism (Noonan syndrome-like disorder / RASopathy)
✓
PM2
moderate
Pathogenic
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.
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0 (HostSeq genomes)
Assessed · not applied
Pathogenic
PS2
No de novo occurrence data with confirmed maternity and paternity are available for this variant in the case materials.
PS3
No well-established in vitro or in vivo functional studies specific to NM_005188.3:c.1096-1_1096delinsTT were identified.
PS4
No data on variant prevalence in affected individuals versus controls.
PM1
The variant affects the intron 7 splice acceptor site.
PM6
No assumed de novo occurrence data (without confirmation of maternity and paternity) are available for this variant.
PP1
No co-segregation data in multiple affected family members are available for this variant.
PP4
No patient phenotype or family history data specific to a disease with a single genetic etiology are available in the case materials.
PP5
The variant is absent from ClinVar; no reputable source has reported this variant as pathogenic.
Benign
BA1
BA1 requires an allele frequency >1% in any general population database (user-specified threshold for non-VCEP assessment).
BS1
BS1 requires an allele frequency >0.3% (user-specified threshold for non-VCEP assessment) — greater than expected for the disorder.
BS2
No data are available on observation of this variant in healthy adult individuals for a fully penetrant dominant disorder.
BS3
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
No segregation data in affected family members are available to assess lack of segregation with disease.
BP2
No data are available on observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact on gene product or splicing.
BP5
No data are available on observation of this variant in a case with an alternate molecular basis for disease.
BP6
The variant is absent from ClinVar; no reputable source has reported this variant as benign.
N/A · 8
PS1 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
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 possible splice impact for this variant (max delta score = 0.99).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links