NM_005188.4:c.1095+19G>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005188.4(CBL):c.1095+19G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.568 in 1,511,976 control chromosomes in the GnomAD database, including 252,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 31059 hom., cov: 32)

Exomes 𝑓: 0.56 ( 221064 hom. )

Consequence

CBL
NM_005188.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -0.253

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 (BayesDel_noAF=-0.86).

BP6

Variant 11-119277863-G-T is Benign according to our data. Variant chr11-119277863-G-T is described in ClinVar as [Benign]. Clinvar id is 55796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119277863-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBL	NM_005188.4 link	c.1095+19G>T		intron_variant	Intron 7 of 15	ENST00000264033.6	NP_005179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6 link	c.1095+19G>T		intron_variant	Intron 7 of 15	1	NM_005188.4	ENSP00000264033.3		P22681

Frequencies

GnomAD3 genomes

AF:

0.623

AC:

94692

AN:

151898

Hom.:

31011

Cov.:

show subpopulations

Gnomad AFR

AF:

0.803

Gnomad AMI

AF:

0.488

Gnomad AMR

AF:

0.463

Gnomad ASJ

AF:

0.641

Gnomad EAS

AF:

0.877

Gnomad SAS

AF:

0.763

Gnomad FIN

AF:

0.568

Gnomad MID

AF:

0.535

Gnomad NFE

AF:

0.532

Gnomad OTH

AF:

0.598

GnomAD3 exomes

AF:

0.588

AC:

147500

AN:

250970

Hom.:

46177

AF XY:

0.597

AC XY:

81035

AN XY:

135646

show subpopulations

Gnomad AFR exome

AF:

0.807

Gnomad AMR exome

AF:

0.355

Gnomad ASJ exome

AF:

0.650

Gnomad EAS exome

AF:

0.881

Gnomad SAS exome

AF:

0.754

Gnomad FIN exome

AF:

0.560

Gnomad NFE exome

AF:

0.536

Gnomad OTH exome

AF:

0.567

GnomAD4 exome

AF:

0.562

AC:

764680

AN:

1359960

Hom.:

221064

Cov.:

AF XY:

0.568

AC XY:

387726

AN XY:

682430

show subpopulations

Gnomad4 AFR exome

AF:

0.813

Gnomad4 AMR exome

AF:

0.370

Gnomad4 ASJ exome

AF:

0.654

Gnomad4 EAS exome

AF:

0.865

Gnomad4 SAS exome

AF:

0.747

Gnomad4 FIN exome

AF:

0.557

Gnomad4 NFE exome

AF:

0.532

Gnomad4 OTH exome

AF:

0.591

GnomAD4 genome

AF:

0.624

AC:

94794

AN:

152016

Hom.:

31059

Cov.:

AF XY:

0.628

AC XY:

46633

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.803

Gnomad4 AMR

AF:

0.463

Gnomad4 ASJ

AF:

0.641

Gnomad4 EAS

AF:

0.877

Gnomad4 SAS

AF:

0.762

Gnomad4 FIN

AF:

0.568

Gnomad4 NFE

AF:

0.532

Gnomad4 OTH

AF:

0.600

Alfa

AF:

0.570

Hom.:

13132

Bravo

AF:

0.622

Asia WGS

AF:

0.803

AC:

2794

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 12, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CBL c.1095+19G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.59 in 250970 control chromosomes, suggesting that it is the major allele and therefore benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CBL-related disorder

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

RASopathy

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in NOONAN panel(s). -

Juvenile myelomonocytic leukemia

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.41

DANN

Benign

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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