rs397517077

Positions:

chr11-119278161-CAAAG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePM2PP3_ModeratePP5_Very_Strong

The NM_005188.4(CBL):c.1096-4_1096-1del variant causes a splice acceptor, splice polypyrimidine tract, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 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, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.60

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.048144065 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.6, offset of -43, new splice context is: gttaacatttataattgcAGtta. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 11-119278161-CAAAG-C is Pathogenic according to our data. Variant chr11-119278161-CAAAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBL	NM_005188.4 linkuse as main transcript	c.1096-4_1096-1del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000264033.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBL	ENST00000264033.6 linkuse as main transcript	c.1096-4_1096-1del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005188.4	P2

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

RASopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2014	This mutation is denoted c.1096-4_1096-1delAAAG (IVS7-4_IVS7-1delAAAG) at the cDNA level. Using lower case letters to denote intronic sequence and capital letters to denote exonic sequence, the normal sequence with the bases that are deleted in braces is: aatc{aaag}GAAC. The c.1096-4_1096_1delAAAG mutation in intron 7 in the CBL gene (NM_005188.2) has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. This mutation has previously been observed at GeneDx in a patient referred for testing of the comprehensive panel for Noonan syndrome and related disorders. The c.1096-4_1096-1delAAAG mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.1096-4_1096-1delAAAG mutation in the CBL gene destroys the splice acceptor site of exon 8, which is an in-frame exon encoding portions of the Zn-finger ring and linker region. The c.1096-4_1096-1delAAAG mutation is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Another splice site mutation that destroys this acceptor site (c.1096-1 G>C) has been reported in a homozygous state in a patient with juvenile myelomonocytic leukemia (JMML), caf? au lait spots, cryptorchidism, juvenile xanthogranuloma, poor growth, and developmental delay (Niemeyer et al., 2010). We interpret c.1096-4_1096-1delAAAG as a disease-causing mutation. The presence of this mutation is consistent with the diagnosis of Noonan syndrome-like disorder. The variant is found in NOONAN panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2022	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 8 or part of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 25952305). ClinVar contains an entry for this variant (Variation ID: 45197). Disruption of this splice site has been observed in individuals with CBL-related conditions (PMID: 25358541, 25952305, 28589114; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 7 of the CBL gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. -

CBL-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Apr 13, 2017

- -

Noonan syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 08, 2012

The 1096-4_1096-1del variant in CBL has not been reported in the literature nor previously identified by our laboratory. This deletion removes 4 base pairs incl uding the invariant region (-1/2) of the splice consensus sequence and is predic ted to cause a likely impact on splicing. Importantly, another variant (1096-1G> C) affecting the same splice site has been identified in a patient with clinical features of Noonan syndrome and juvenile myelomonocytic leukemia (Niemeyer 2010 ). Loss of this splice site has been shown to cause skipping of exon 8 or retent ion of intron 7, resulting in proteins that lack essential regions of the linker and ring finger domains (Niemeyer 2010). Loss of CBL function results in Ras hy peractivation, which is associated with Noonan syndrome-like disorder with or wi thout JMML. In summary, the 1096-4-1096-1del variant in CBL is likely to be path ogenic, though additional studies are required to fully establish its pathogenic ity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AL_spliceai