chr11-119278165-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_005188.4(CBL):c.1096-1G>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,916 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (★★).
Frequency
Consequence
NM_005188.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CBL | NM_005188.4 | c.1096-1G>T | splice_acceptor_variant, intron_variant | Intron 7 of 15 | ENST00000264033.6 | NP_005179.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151916Hom.: 0 Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1438558Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 716956
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151916Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74156
ClinVar
Submissions by phenotype
CBL-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Mar 25, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 05, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 20694012, 25358541, 26796102, 25952305, 20595524, 23823657, 28589114, 34345822, 30417923, 31935506, 20619386, 22315494, 25533962) - |
Noonan syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 26, 2016 | The c.1096-1G>T variant in CBL has been previously reported in as a de novo, con stitutional (germline) variant in 2 individuals with a RASopathy disorder and a somatic variant in 1 individual with JMML (Matsuda 2010, Bulow 2015, Martinelli 2015). It was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Three additiona l disease-causing variants affecting the same position (c.1096-1G>C, c.1096-1del GG, and c.1096-1delGAAA) have been previously reported in individuals with clini cal features of Noonan syndrome (Niemeyer 2010, Strullu 2013, Bulow 2015, Martin elli 2015). In vitro studies provide some evidence for exon 8 skipping for the c .1096-1G>T variant (Martinelli 2015). In summary, this variant meets our criteri a to be classified as pathogenic for Noonan syndrome in an autosomal dominant ma nner based upon de novo occurrences, absence from controls, and functional evide nce. - |
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 01, 2020 | This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this splice variant disrupts the canonical splice site and causes the in-frame skipping of exon 8 (PMID: 25952305). This variant has been observed in individual(s) affected with Noonan or Noonan-like syndrome (PMID: 25358541, 28589114, 25952305, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 180815). This sequence change affects an acceptor splice site in intron 7 of the CBL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. - |
CBL-related disorder;CN296118:Fragile site 11b Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as Pathogenic and reported on 02-15-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at