NM_005188.4:c.125_127delACC

Variant names:

• chr11-119206522-GCAC-G
• rs373212940
• NM_005188.4:c.125_127delACC

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO4_SupportingO9_Moderate

The NM_005188.4(CBL):c.125_127delACC (p.His42del) variant causes a disruptive inframe deletion change. The variant results in an in-frame change. The gene CBL is a tumor suppressor gene (CancerMine: 6 TSG, 61 oncogene, 11 driver citations). The gene CBL is a known oncogene (CancerMine: 6 TSG, 61 oncogene, 11 driver citations). The gene CBL is a cancer driver gene (CancerMine: 6 TSG, 61 oncogene, 11 driver citations). The variant allele was found at a cumulative frequency of 0.00000659 (AC=1) in the gnomAD database across 151,838 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000265. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). The variant has been observed in cBioPortal in 7 samples across 6 studies and 5 cancer types; somatic enrichment level: SUPPORTING (Observed repeatedly in cBioPortal somatic datasets.).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: CBL NM_005188.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.20
• Publications: 4 publications found

Genes affected

CBL (HGNC:1541): (Cbl proto-oncogene) This gene is a proto-oncogene that encodes a RING finger E3 ubiquitin ligase. The encoded protein is one of the enzymes required for targeting substrates for degradation by the proteasome. This protein mediates the transfer of ubiquitin from ubiquitin conjugating enzymes (E2) to specific substrates. This protein also contains an N-terminal phosphotyrosine binding domain that allows it to interact with numerous tyrosine-phosphorylated substrates and target them for proteasome degradation. As such it functions as a negative regulator of many signal transduction pathways. This gene has been found to be mutated or translocated in many cancers including acute myeloid leukaemia, and expansion of CGG repeats in the 5' UTR has been associated with Jacobsen syndrome. Mutations in this gene are also the cause of Noonan syndrome-like disorder. [provided by RefSeq, Jul 2016]

CBL Gene-Disease associations (from GenCC):

• CBL-related disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• juvenile myelomonocytic leukemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000265, AC = 1 — absent/extremely rare (O3 moderate [+2])
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 1.0) — Supporting (O4); cBioPortal: samples=7 | studies=6 | cancer types=5 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.
	O9Protein length change in non-repeat region		In-frame indel in non-repetitive region of known cancer gene (O9 moderate); In-frame indel in non-repetitive region — gene: oncogene/TSG

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005188.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CBL NM_005188.4	MANE Select	c.125_127delACC p.His42del	disruptive_inframe_deletion	Exon 1 of 16	Prot: NP_005179.2

CBL NM_005188.4

MANE Select

HGVSc / HGVSpc.125_127delACCp.His42del

Exon rankExon 1 of 16

disruptive_inframe_deletion

Prot: NP_005179.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CBL ENST00000264033.6	TSL:1MANE Select	c.125_127delACC p.His42del	disruptive_inframe_deletion	Exon 1 of 16	Prot: ENSP00000264033.3 UniProt:
	CBL ENST00000634586.1	TSL:5	c.125_127delACC p.His42del	disruptive_inframe_deletion	Exon 1 of 18	Prot: ENSP00000489218.1 UniProt:
	CBL ENST00000637974.1	TSL:5	c.119_121delACC p.His40del	disruptive_inframe_deletion	Exon 1 of 17	Prot: ENSP00000490763.1 UniProt:

CBL ENST00000264033.6

TSL:1MANE Select

HGVSc / HGVSpc.125_127delACCp.His42del

Exon rankExon 1 of 16

disruptive_inframe_deletion

Prot: ENSP00000264033.3UniProt: P22681

CBL ENST00000634586.1

TSL:5

HGVSc / HGVSpc.125_127delACCp.His42del

Exon rankExon 1 of 18

disruptive_inframe_deletion

Prot: ENSP00000489218.1UniProt: A0A0U1RQX8

CBL ENST00000637974.1

TSL:5

HGVSc / HGVSpc.119_121delACCp.His40del

Exon rankExon 1 of 17

disruptive_inframe_deletion

Prot: ENSP00000490763.1UniProt: A0A1B0GW38

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000659	AC:1	Hom:0	AN:151838	Cov:32
GnomAD2 exomes	AF: 0.000665	AC:101	Hom:	AN:151840	Cov:
GnomAD4 exome Warning	AF: 0.0000995	AC:139	Hom:0	AN:1396618	Cov:
GnomAD4 genome	AF: 0.00000659	AC:1	Hom:0	AN:151838	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00183	AC:61	Hom:0	AN:33382	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00257	AC:6	Hom:0	AN:2334	Cov:
Korea4K (4,157 Koreans)	AF: 0.000978	AC:7	Hom:	AN:7160	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000357	1	28048	0.0000352	1	28436

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	2	RASopathy (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	-	1	Juvenile myelomonocytic leukemia;C3150803:CBL-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	43/57	disease causing
PhyloP100	Benign	1.2

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 1 of 1 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs373212940;

hg19: chr11-119077232;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar