rs150811339
Positions:
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_005188.4(CBL):c.2363G>A(p.Arg788Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,614,180 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).
Frequency
Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
CBL
NM_005188.4 missense
NM_005188.4 missense
Scores
2
10
7
Clinical Significance
Conservation
PhyloP100: 8.62
Genes affected
CBL (HGNC:1541): (Cbl proto-oncogene) This gene is a proto-oncogene that encodes a RING finger E3 ubiquitin ligase. The encoded protein is one of the enzymes required for targeting substrates for degradation by the proteasome. This protein mediates the transfer of ubiquitin from ubiquitin conjugating enzymes (E2) to specific substrates. This protein also contains an N-terminal phosphotyrosine binding domain that allows it to interact with numerous tyrosine-phosphorylated substrates and target them for proteasome degradation. As such it functions as a negative regulator of many signal transduction pathways. This gene has been found to be mutated or translocated in many cancers including acute myeloid leukaemia, and expansion of CGG repeats in the 5' UTR has been associated with Jacobsen syndrome. Mutations in this gene are also the cause of Noonan syndrome-like disorder. [provided by RefSeq, Jul 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -11 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.13251954).
BP6
Variant 11-119298469-G-A is Benign according to our data. Variant chr11-119298469-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180823.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000322 (49/152308) while in subpopulation AFR AF= 0.00103 (43/41566). AF 95% confidence interval is 0.000789. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 49 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CBL | NM_005188.4 | c.2363G>A | p.Arg788Gln | missense_variant | 15/16 | ENST00000264033.6 | NP_005179.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CBL | ENST00000264033.6 | c.2363G>A | p.Arg788Gln | missense_variant | 15/16 | 1 | NM_005188.4 | ENSP00000264033.3 |
Frequencies
GnomAD3 genomes AF: 0.000322 AC: 49AN: 152190Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000111 AC: 28AN: 251456Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135904
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GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19AN XY: 727238
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GnomAD4 genome AF: 0.000322 AC: 49AN: 152308Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23AN XY: 74482
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 22, 2022 | Variant summary: CBL c.2363G>A (p.Arg788Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251456 control chromosomes. The observed variant frequency is approximately 45 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.2363G>A in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign/benign, n=2; VUS, n=1). 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 | Jun 18, 2021 | DNA sequence analysis of the CBL gene demonstrated a sequence change, c.2363G>A, in exon 15 that results in an amino acid change, p.Arg788Gln. This sequence change has been described in the gnomAD database with a frequency of 0.08% in the African American/African subpopulation (dbSNP rs150811339). The p.Arg788Gln change affects a moderately conserved amino acid residue located in a domain of the CBL protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg788Gln substitution. This sequence change does not appear to have been previously described in patients with CBL-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg788Gln change remains unknown at this time. - |
not provided Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 04, 2020 | - - |
RASopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;.;.
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;.
Sift4G
Benign
T;T;T;.;T
Polyphen
D;.;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at