rs727504426

chr11-119278508-A-Gchr11-119278508-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_005188.4(CBL):c.1228-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CBL NM_005188.4 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.92

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.07460492 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-119278508-A-G is Pathogenic according to our data. Variant chr11-119278508-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119278508-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBL	NM_005188.4	c.1228-2A>G		splice_acceptor_variant		ENST00000264033.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBL	ENST00000264033.6	c.1228-2A>G		splice_acceptor_variant		1	NM_005188.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Juvenile myelomonocytic leukemia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 23, 2020	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 04, 2014	The 1228-2A>G variant in CBL has previously been identified in 5 individuals wit h juvenile myelomonocytic leukemia (JMML; Niemeyer 2010, Perez 2010, Park 2012, Loh 2009), in each of whom it was identified in the homozygous state in the leuk emia cells. At least one of these individuals also had clinical features of a No onan spectrum disorder, and this variant was not identified in either parent of this individual and likely occurred de novo (Niemeyer 2010). In addition, this v ariant was absent from large population studies. Studies have shown that the 122 8-2A>G variant is leads to deletion of exon 9 and is predicted to encode a prote in that lacks essential regions of the linker and RING finger domains (Niemeyer 2010). In summary, this variant meets our criteria to be classified as pathogeni c for JMML, based on presence in the homozygous state in the leukemia cells mult iple individuals with JMML and predicted impact to the protein (http://pcpgm.par tners.org/LMM). -

Malignant germ cell tumor of ovary Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Apr 04, 2017

This is a splice site alteration in which an A is replaced by a G in intron 8, two nucleotides upstream from the beginning of exon 9. Classification criteria: PVS1, PM2. -

Noonan syndrome-like disorder with juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2010

- -

CBL-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000177959). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 06, 2022

Identified as homozygous in peripheral blood of patients with juvenile myelomonocytic leukemia (JMML). In one patient with additional features of poor growth and developmental delay, variant was heterozygous in normal tissues and presumed to be germline (Loh et al., 2009; Niemayer et al., 2010).; Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in an in-frame deletion of a critical region (part of RING-Type zinc finger and linker region); This variant is associated with the following publications: (PMID: 32637631, 21901340, 20694012, 20955399, 23823657, 28343148, 34026204, 20619386, 22315494, 19571318) -

Noonan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 04, 2014

The 1228-2A>G variant in CBL has previously been identified in 5 individuals wit h juvenile myelomonocytic leukemia (JMML; Niemeyer 2010, Perez 2010, Park 2012, Loh 2009), in each of whom it was identified in the homozygous state in the leuk emia cells. At least one of these individuals also had clinical features of a No onan spectrum disorder, and this variant was not identified in either parent of this individual and likely occurred de novo (Niemeyer 2010). In addition, this v ariant was absent from large population studies. Studies have shown that the 122 8-2A>G variant is leads to deletion of exon 9 and is predicted to encode a prote in that lacks essential regions of the linker and RING finger domains (Niemeyer 2010). In summary, this variant is likely to be pathogenic, though additional st udies are required to fully establish its clinical significance. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2023

This sequence change affects an acceptor splice site in intron 8 of the CBL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CBL cause disease. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of CBL-related conditions (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177959). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.87		Position offset: 9
DS_AL_spliceai		1.0		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504426; hg19: chr11-119149218; COSMIC: COSV50629953;