11-119277863-G-T

Position:

• chr11-119277863-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000264033.6(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 ENST00000264033.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.253

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]

ACMG classification

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/exons	MANE	Protein	UniProt
CBL	NM_005188.4	c.1095+19G>T		intron_variant		ENST00000264033.6	NP_005179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6	c.1095+19G>T		intron_variant		1	NM_005188.4	ENSP00000264033	P2

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94692 AN: 151898 Hom.: 31011 Cov.: 32

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

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.: 22 AF XY: 0.568 AC XY: 387726 AN XY: 682430

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.: 32 AF XY: 0.628 AC XY: 46633 AN XY: 74290

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:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2019	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -

CBL-related disorder Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

RASopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2012	The variant is found in NOONAN panel(s). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Juvenile myelomonocytic leukemia Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

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

Other links and lift over

dbSNP: rs2510152; hg19: chr11-119148573; COSMIC: COSV50630143;