rs746795014
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_005188.4(CBL):c.2614C>A(p.Gln872Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000712 in 1,614,074 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q872E) has been classified as Uncertain significance.
Frequency
Consequence
NM_005188.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBL | NM_005188.4 | c.2614C>A | p.Gln872Lys | missense_variant | 16/16 | ENST00000264033.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBL | ENST00000264033.6 | c.2614C>A | p.Gln872Lys | missense_variant | 16/16 | 1 | NM_005188.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251470Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135904
GnomAD4 exome AF: 0.0000752 AC: 110AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.0000811 AC XY: 59AN XY: 727240
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74362
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 | Feb 28, 2018 | Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: GnomAd 11:119170384 C / A: Europeans 5/111684; fairly- well conserved, but lysine seen in cavefish; Not in ClinVar, Pubmed, Google search or HGMD; possibly damaging by polyphen - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 19, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with childhood acute lymphoblastic leukemia (de Smith 2019); This variant is associated with the following publications: (PMID: 31102422) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 12, 2023 | The p.Q872K variant (also known as c.2614C>A), located in coding exon 16 of the CBL gene, results from a C to A substitution at nucleotide position 2614. The glutamine at codon 872 is replaced by lysine, an amino acid with similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with acute lymphocytic leukemia (ALL) (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). Additionally, this alteration was reported as a putative germline alteration of interest identified in 1/57 HD-ALL patients from the California Childhood Leukemia study who were tested via targeted multi-gene panel testing. (de Smith AJ et al. Genes Chromosomes Cancer, 2019 Oct;58:723-730). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 13, 2023 | 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. This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 31102422). This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 872 of the CBL protein (p.Gln872Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. ClinVar contains an entry for this variant (Variation ID: 503534). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CBL protein function. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at