rs777761446
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM4_SupportingBS2
The ENST00000264033.6(CBL):c.2414_2416dup(p.Leu805_Asp806insVal) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.00000743 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
CBL
ENST00000264033.6 inframe_insertion
ENST00000264033.6 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.99
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in ENST00000264033.6. Strenght limited to Supporting due to length of the change: 1aa.
BS2
High AC in GnomAdExome4 at 10 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CBL | NM_005188.4 | c.2414_2416dup | p.Leu805_Asp806insVal | inframe_insertion | 15/16 | ENST00000264033.6 | NP_005179.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CBL | ENST00000264033.6 | c.2414_2416dup | p.Leu805_Asp806insVal | inframe_insertion | 15/16 | 1 | NM_005188.4 | ENSP00000264033 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251456Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135914
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727236
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74362
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Noonan-like syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 24, 2022 | In-frame insertion of 1 amino acid in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11067845) - |
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 12, 2023 | This variant, c.2414_2416dup, results in the insertion of 1 amino acid(s) of the CBL protein (p.Leu805_Asp806insVal), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs777761446, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 302787). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at