11-119297446-C-T

Position:

chr11-119297446-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.2216C>T(p.Ser739Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000272 in 1,613,272 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 3 hom. )

Consequence

CBL
NM_005188.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.52

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=0.012963235).

BP6

Variant 11-119297446-C-T is Benign according to our data. Variant chr11-119297446-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 40418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119297446-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000138 (21/151930) while in subpopulation SAS AF= 0.0021 (10/4768). AF 95% confidence interval is 0.00114. There are 1 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBL	NM_005188.4 linkuse as main transcript	c.2216C>T	p.Ser739Phe	missense_variant	14/16	ENST00000264033.6	NP_005179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6 linkuse as main transcript	c.2216C>T	p.Ser739Phe	missense_variant	14/16	1	NM_005188.4	ENSP00000264033	P2

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

151812

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00210

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000438

AC:

110

AN:

251278

Hom.:

AF XY:

0.000574

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00206

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000286

AC:

418

AN:

1461342

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

264

AN XY:

727000

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00213

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000163

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000138

AC:

AN:

151930

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00210

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000883

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000280

Hom.:

Bravo

AF:

0.000162

ExAC

AF:

0.000511

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2017	p.Ser739Phe in exon 14 of CBL: This variant is not expected to have clinical sig nificance because it has been identified in 0.2% (38/16502) of South Asian chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs2227986). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 01, 2023	- -

CBL-related disorder

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 20, 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). -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	CBL: BS1 -

Noonan syndrome and Noonan-related syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 07, 2020

- -

RASopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Uncertain

0.44

T;.;T;.

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.1

M;.;.;.

MutationTaster

Benign

0.96

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.73

N;.;.;.

REVEL

Benign

0.23

Sift

Uncertain

0.0040

D;.;.;.

Sift4G

Uncertain

0.012

D;D;D;.

Polyphen

0.37

B;.;.;.

Vest4

0.48

MVP

0.90

MPC

0.36

ClinPred

0.028

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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