CBL c.1235_1273dup, p.Glu412_Lys424dup
NM_005188.3:c.1235_1273dup
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
CBL
Transcript
NM_005188.4
MANE Select
Total Exons
16
Strand
Forward (+)
Reference Sequence
NC_000011.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_005188.3 | RefSeq Select | 16 exons | Forward |
| NM_005188.2 | Alternative | 16 exons | Forward |
Variant Details
HGVS Notation
NM_005188.3:c.1235_1273dup
Protein Change
E412_K424dup
Location
Exon 9
(Exon 9 of 16)
5'
Exon Structure (16 total)
3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_005188.4
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications
0 publications
Clinical Statement
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Functional Studies
Summary
The CBL E412_K424dup variant has not been functionally characterized, and its biological significance remains unknown.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
PVS1
PVS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence for this variant shows: it is an in-frame duplication (E412_K424dup), not predicted to result in a null effect. Therefore, this criterion is not applied because the variant does not create a null allele.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant but different nucleotide change'. The evidence for this variant shows: no known pathogenic variant causes the same protein change. Therefore, this criterion is not applied because there is no matching established pathogenic variant.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: no data on de novo occurrence. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: no functional studies have characterized this duplication. Therefore, this criterion is not applied due to absence of functional evidence.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: no case-control or patient prevalence data. Therefore, this criterion is not applied due to lack of statistical association data.
PM1
PM1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: location relative to functional domains or hot spots is unknown. Therefore, this criterion is not applied due to missing domain context.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: not found in gnomAD or other population databases (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for recessive disorders'. The evidence for this variant shows: no information on phasing or trans configuration. Therefore, this criterion is not applied due to lack of allele phasing data.
PM4
PM4 (Moderate)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: an in-frame duplication of amino acids E412_K424 resulting in altered protein length. Therefore, this criterion is applied at Moderate strength because the variant leads to a protein length change.
PM5
PM5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows: this is an in-frame duplication, not a missense change. Therefore, this criterion is not applied as it is not a missense variant.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no data on de novo status. Therefore, this criterion is not applied due to absence of assumed de novo information.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: no family segregation data available. Therefore, this criterion is not applied due to lack of segregation analysis.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: it is an in-frame duplication, not a missense change. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene/gene product'. The evidence for this variant shows: in silico predictions and SpliceAI analysis are inconclusive. Therefore, this criterion is not applied due to lack of supportive computational evidence.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no detailed phenotype or family history provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: no external pathogenic assertions found in databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder'. The evidence for this variant shows: allele frequency is 0% in population databases. Therefore, this criterion is not applied because the variant is not too frequent.
BS1
BS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for disorder'. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied due to insufficient frequency.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age'. The evidence for this variant shows: no observations in healthy individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence for this variant shows: no family data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss of function causes disease'. The evidence for this variant shows: it is an in-frame duplication, not a missense variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant'. The evidence for this variant shows: no phasing data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame insertions/deletions in a repetitive region without known function'. The evidence for this variant shows: region repetitive status unknown. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence for this variant shows: computational predictions are inconclusive. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no such cases reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: no external benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.