chr11-119206522-G-GCACCAC
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_005188.4(CBL):c.122_127dup(p.His41_His42dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,556,406 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P35P) has been classified as Likely benign.
Frequency
Consequence
NM_005188.4 inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBL | NM_005188.4 | c.122_127dup | p.His41_His42dup | inframe_insertion | 1/16 | ENST00000264033.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBL | ENST00000264033.6 | c.122_127dup | p.His41_His42dup | inframe_insertion | 1/16 | 1 | NM_005188.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 151854Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000724 AC: 11AN: 151840Hom.: 0 AF XY: 0.0000740 AC XY: 6AN XY: 81094
GnomAD4 exome AF: 0.000179 AC: 252AN: 1404552Hom.: 0 Cov.: 32 AF XY: 0.000172 AC XY: 119AN XY: 693484
GnomAD4 genome ? AF: 0.000125 AC: 19AN: 151854Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12AN XY: 74174
ClinVar
Submissions by phenotype
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 02, 2019 | - - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 05, 2021 | Variant summary: CBL c.122_127dupACCACC (p.His41_His42dup) results in an in-frame duplication that is predicted to duplicate 2 amino acids into the encoded protein. The variant allele was found at a frequency of 7.2e-05 in 151840 control chromosomes. The observed variant frequency is approximately 29 fold of the estimated maximal expected allele frequency for a pathogenic variant in CBL causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.122_127dupACCACC in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been reported ( Internal data; PTPN11 c.854T>C, p.Phe285Ser), providing supporting evidence for a benign role. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 14, 2019 | - - |
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This variant, c.122_127dup, results in the insertion of 2 amino acid(s) of the CBL protein (p.His41_His42dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs373212940, gnomAD 0.03%). This variant has been observed in individual(s) with clinical features of Noonan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 477693). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
CBL-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 10, 2020 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at