11-119285483-C-T

Position:

chr11-119285483-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005188.4(CBL):c.1858C>T(p.Leu620Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00178 in 1,614,204 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L620V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 65 hom. )

Consequence

CBL
NM_005188.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: 7.07

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]

CBL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007474512).

BP6

Variant 11-119285483-C-T is Benign according to our data. Variant chr11-119285483-C-T is described in ClinVar as [Benign]. Clinvar id is 45203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119285483-C-T is described in Lovd as [Benign]. Variant chr11-119285483-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00194 (296/152360) while in subpopulation EAS AF= 0.0403 (209/5192). AF 95% confidence interval is 0.0358. There are 5 homozygotes in gnomad4. There are 169 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 296 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBL	NM_005188.4 linkuse as main transcript	c.1858C>T	p.Leu620Phe	missense_variant	11/16	ENST00000264033.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBL	ENST00000264033.6 linkuse as main transcript	c.1858C>T	p.Leu620Phe	missense_variant	11/16	1	NM_005188.4	P2

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

296

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.0402

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00301

AC:

756

AN:

251406

Hom.:

AF XY:

0.00282

AC XY:

383

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.0334

Gnomad SAS exome

AF:

0.00157

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00176

AC:

2573

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

1276

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00341

Gnomad4 EAS exome

AF:

0.0477

Gnomad4 SAS exome

AF:

0.00181

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.00550

GnomAD4 genome

AF:

0.00194

AC:

296

AN:

152360

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

169

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00433

Gnomad4 EAS

AF:

0.0403

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.0235

Hom.:

2364

Bravo

AF:

0.00169

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00287

AC:

349

Asia WGS

AF:

0.0420

AC:

144

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 03, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 26, 2016	p.Leu620Phe in Exon 11 of CBL: This variant is not expected to have clinical sig nificance because it has been identified in 3.3% (286/8638) of East Asian chromo somes (including 2 homozygous individuals) by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs2227988). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2013	This 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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 29, 2019	Variant summary: CBL c.1858C>T (p.Leu620Phe) results in a non-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 0.003 in 251406 control chromosomes, predominantly at a frequency of 0.033 within the East Asian subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 13200-folds over 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 a benign polymorphism found primarily in populations of East Asian origin. Three ClinVar submissions (evaluation after 2014) cite the variant twice as benign and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Juvenile myelomonocytic leukemia;C3150803:CBL-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 19, 2021

- -

CBL-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This 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 submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2020

This 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 submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 16, 2021

- -

RASopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;.;T;.

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;D;D;D

MetaRNN

Benign

0.0075

T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.2

M;.;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.66

N;.;.;.

REVEL

Uncertain

0.33

Sift

Benign

0.044

D;.;.;.

Sift4G

Benign

0.48

T;T;T;.

Polyphen

1.0

D;.;.;.

Vest4

0.81

MVP

0.93

MPC

0.71

ClinPred

0.013

GERP RS

5.2

Varity_R

0.17

gMVP

0.31

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over