11-119277863-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

CBL-related disorder
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, Genomics England PanelApp
juvenile myelomonocytic leukemia
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Noonan syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CBL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 55796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

GnomAD2 exomes

AF:

0.588

AC:

147500

AN:

250970

AF XY:

0.597

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 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

African (AFR)

AF:

0.813

AC:

25616

AN:

31504

American (AMR)

AF:

0.370

AC:

16511

AN:

44582

Ashkenazi Jewish (ASJ)

AF:

0.654

AC:

16696

AN:

25524

East Asian (EAS)

AF:

0.865

AC:

33941

AN:

39232

South Asian (SAS)

AF:

0.747

AC:

62932

AN:

84230

European-Finnish (FIN)

AF:

0.557

AC:

29726

AN:

53362

Middle Eastern (MID)

AF:

0.612

AC:

3409

AN:

5570

European-Non Finnish (NFE)

AF:

0.532

AC:

542112

AN:

1018892

Other (OTH)

AF:

0.591

AC:

33737

AN:

57064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

15796

31593

47389

63186

78982

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15134

30268

45402

60536

75670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.624

AC:

94794

AN:

152016

Hom.:

31059

Cov.:

AF XY:

0.628

AC XY:

46633

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.803

AC:

33306

AN:

41480

American (AMR)

AF:

0.463

AC:

7069

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.641

AC:

2223

AN:

3470

East Asian (EAS)

AF:

0.877

AC:

4525

AN:

5160

South Asian (SAS)

AF:

0.762

AC:

3672

AN:

4820

European-Finnish (FIN)

AF:

0.568

AC:

5984

AN:

10532

Middle Eastern (MID)

AF:

0.541

AC:

158

AN:

292

European-Non Finnish (NFE)

AF:

0.532

AC:

36144

AN:

67958

Other (OTH)

AF:

0.600

AC:

1270

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1710

3420

5131

6841

8551

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

772

1544

2316

3088

3860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.570

Hom.:

21587

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

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CBL-related disorder

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

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

(source)

DANN

Benign

0.31

PhyloP100

-0.25

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over