rs730880429
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_005188.4(CBL):c.202C>T(p.Arg68Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R68Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_005188.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBL | NM_005188.4 | c.202C>T | p.Arg68Trp | missense_variant | 2/16 | ENST00000264033.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBL | ENST00000264033.6 | c.202C>T | p.Arg68Trp | missense_variant | 2/16 | 1 | NM_005188.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250494Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135518
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461206Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726908
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Juvenile myelomonocytic leukemia;C3150803:CBL-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 27, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 26, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18034775, 20619386) - |
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 05, 2021 | In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CBL-related disease. ClinVar contains an entry for this variant (Variation ID: 180811). This sequence change replaces arginine with tryptophan at codon 68 of the CBL protein (p.Arg68Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at