rs143132980
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4BP6BS1BS2
The NM_005188.4(CBL):c.2359C>T(p.Arg787Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000768 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R787H) has been classified as Likely benign.
Frequency
Consequence
NM_005188.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBL | NM_005188.4 | c.2359C>T | p.Arg787Cys | missense_variant | 15/16 | ENST00000264033.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBL | ENST00000264033.6 | c.2359C>T | p.Arg787Cys | missense_variant | 15/16 | 1 | NM_005188.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000215 AC: 54AN: 251470Hom.: 0 AF XY: 0.000191 AC XY: 26AN XY: 135908
GnomAD4 exome AF: 0.0000739 AC: 108AN: 1461850Hom.: 0 Cov.: 32 AF XY: 0.0000715 AC XY: 52AN XY: 727238
GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74326
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 02, 2014 | The Arg787Cys variant in CBL has not been previously reported in individuals wit h Noonan syndrome, but has been identified in 1/8590 of European American chromo somes and in 2/4398 of African American chromosomes by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu; dbSNP rs143132980). Computational predi ction tools and conservation analysis suggest that the Arg787 variant may impact the protein, though this information is not predictive enough to determine path ogenicity. In summary, the clinical significance of the Arg787Cys variant is unc ertain. - |
Noonan syndrome and Noonan-related syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | May 01, 2020 | - - |
CBL-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 29, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
RASopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at