rs34777499

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005188.4(CBL):​c.1485G>A​(p.Pro495=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,614,022 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P495P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0056 ( 8 hom., cov: 32)
Exomes 𝑓: 0.0022 ( 36 hom. )

Consequence

CBL
NM_005188.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -3.30
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
Variant 11-119285022-G-A is Benign according to our data. Variant chr11-119285022-G-A is described in ClinVar as [Benign]. Clinvar id is 45201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119285022-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-3.3 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00561 (853/152142) while in subpopulation SAS AF= 0.016 (77/4824). AF 95% confidence interval is 0.0147. There are 8 homozygotes in gnomad4. There are 422 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 853 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CBLNM_005188.4 linkuse as main transcriptc.1485G>A p.Pro495= synonymous_variant 10/16 ENST00000264033.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CBLENST00000264033.6 linkuse as main transcriptc.1485G>A p.Pro495= synonymous_variant 10/161 NM_005188.4 P2

Frequencies

GnomAD3 genomes
AF:
0.00560
AC:
852
AN:
152024
Hom.:
8
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0157
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00210
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0159
Gnomad FIN
AF:
0.000378
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00118
Gnomad OTH
AF:
0.00432
GnomAD3 exomes
AF:
0.00396
AC:
996
AN:
251470
Hom.:
11
AF XY:
0.00422
AC XY:
574
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.0163
Gnomad AMR exome
AF:
0.00107
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0169
Gnomad FIN exome
AF:
0.000185
Gnomad NFE exome
AF:
0.00124
Gnomad OTH exome
AF:
0.00489
GnomAD4 exome
AF:
0.00216
AC:
3159
AN:
1461880
Hom.:
36
Cov.:
33
AF XY:
0.00243
AC XY:
1767
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0178
Gnomad4 AMR exome
AF:
0.00114
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0156
Gnomad4 FIN exome
AF:
0.000150
Gnomad4 NFE exome
AF:
0.000841
Gnomad4 OTH exome
AF:
0.00338
GnomAD4 genome
AF:
0.00561
AC:
853
AN:
152142
Hom.:
8
Cov.:
32
AF XY:
0.00567
AC XY:
422
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.0157
Gnomad4 AMR
AF:
0.00209
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0160
Gnomad4 FIN
AF:
0.000378
Gnomad4 NFE
AF:
0.00118
Gnomad4 OTH
AF:
0.00428
Alfa
AF:
0.00292
Hom.:
1
Bravo
AF:
0.00615
Asia WGS
AF:
0.0160
AC:
57
AN:
3478
EpiCase
AF:
0.00147
EpiControl
AF:
0.00142

ClinVar

Significance: Benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:8
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 28, 2012This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 19, 2012p.Pro495Pro in Exon 10 of CBL: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 1.3% (47/3738) of Afri can American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs34777499). -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 21, 2019- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesDec 19, 2022- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
CBL-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Juvenile myelomonocytic leukemia Benign:1
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 04, 2019This alteration is classified as 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. -
Noonan syndrome and Noonan-related syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJun 18, 2021- -
RASopathy Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.52
CADD
Benign
3.8
DANN
Benign
0.85
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2229072; hg19: chr11-119155732; COSMIC: COSV50634231; COSMIC: COSV50634231; API