Classification rationale

PM2 VUS

CBL c.1147A>G

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.¹ 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 v1.0.² 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 0.01.³

PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 revelbayesdelspliceai ↗

Gene diagram · NM_005188.3 · variants mapped to exon structure

CBL NM_005188.3

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.8611e-06; MAF= 0.00019%, 3/1611950 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.334e-05; MAF= 0.00333%, 2/59988 alleles, homozygotes = 0); grpmax FAF= 5.53e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.97943e-06; MAF= 0.00040%, 1/251292 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89118e-05; MAF= 0.00289%, 1/34588 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,611,950
0 hom · FAF 0.00055%

Admixed American 2 / 59,988	0.0033%
European (non-Finnish) 1 / 1,178,132	8.5e-05%

+ 8 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0004% · 1 / 251,292
0 hom

Admixed American

1 / 34,588

0.0029%

+ 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 4804130)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.605. BayesDel score = 0.0719745.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CBL, a tumor suppressor and ubiquitin ligase, is inactivated by mutation or deletion in various cancer types including myeloid malignancies.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 1 PMID not cited in assessment

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR