Genetic Variant NM_005188.4:c.119_127delACCACCACC (chr11-119206522-GCACCACCAC-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is The variant received 3 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingPM4

The NM_005188.4(CBL):c.119_127delACCACCACC (p.His40_His42del) variant causes a disruptive inframe deletion change. The variant results in an in-frame change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant allele was found at a cumulative frequency of 0.0000198 (AC=3) in the gnomAD database across 151,854 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000217. 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. Variant has been reported in ClinVar as Uncertain Significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CBL
NM_005188.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.31

Publications

4 publications found

Variant links:

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

CBL links:

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new If you want to explore the variant's impact on the transcript NM_005188.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Show applied only (2)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000217 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
	PM4Protein length change in non-repeat region		In-frame indel in non-repetitive region — protein length change (PM4); In-frame indel in non-repetitive region — protein length change (3 AA).

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.119_127delACCACCACC p.His40_His42del	disruptive_inframe_deletion	Exon 1 of 16	Prot: NP_005179.2

CBL NM_005188.4

MANE Select

HGVSc / HGVSpc.119_127delACCACCACCp.His40_His42del

Exon rankExon 1 of 16

disruptive_inframe_deletion

Prot: NP_005179.2

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
CBL ENST00000264033.6	TSL:1MANE Select	c.119_127delACCACCACC p.His40_His42del	disruptive_inframe_deletion	Exon 1 of 16	Prot: ENSP00000264033.3 UniProt: P22681
CBL ENST00000634586.1	TSL:5	c.119_127delACCACCACC p.His40_His42del	disruptive_inframe_deletion	Exon 1 of 18	Prot: ENSP00000489218.1 UniProt: A0A0U1RQX8
CBL ENST00000637974.1	TSL:5	c.113_121delACCACCACC p.His38_His40del	disruptive_inframe_deletion	Exon 1 of 17	Prot: ENSP00000490763.1 UniProt: A0A1B0GW38

CBL ENST00000264033.6

TSL:1MANE Select

HGVSc / HGVSpc.119_127delACCACCACCp.His40_His42del

Exon rankExon 1 of 16

disruptive_inframe_deletion

Prot: ENSP00000264033.3UniProt: P22681

CBL ENST00000634586.1

TSL:5

HGVSc / HGVSpc.119_127delACCACCACCp.His40_His42del

Exon rankExon 1 of 18

disruptive_inframe_deletion

Prot: ENSP00000489218.1UniProt: A0A0U1RQX8

CBL ENST00000637974.1

TSL:5

HGVSc / HGVSpc.113_121delACCACCACCp.His38_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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000198	AC:3	Hom:0	AN:151854	Cov:32
GnomAD4 exome Warning	AF: 0.0000150	AC:21	Hom:0	AN:1404552	Cov:
GnomAD4 genome	AF: 0.0000198	AC:3	Hom:0	AN:151854	Cov:32
TOPMed (Bravo)	AF: 0.0000227	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:33382	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

RASopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	84/116	disease causing
PhyloP100	Uncertain	5.3

Showing 2 of 2 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence