chr11-119300340-T-TC

Variant names:

• chr11-119300340-T-TC
• rs3833768
• NM_005188.4:c.*559_*560insC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005188.4(CBL):​c.*559_*560insC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 410,686 control chromosomes in the GnomAD database, including 14,251 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4644 hom., cov: 32)
  • Exomes 𝑓: 0.27 (9607 hom.)
• Consequence: CBL NM_005188.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00700
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 11-119300340-T-TC is Benign according to our data. Variant chr11-119300340-T-TC is described in ClinVar as Likely_benign. ClinVar VariationId is 210588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005188.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBL	NM_005188.4	MANE Select	c.*559_*560insC		3_prime_UTR	Exon 16 of 16	NP_005179.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBL	ENST00000264033.6	TSL:1 MANE Select	c.*559_*560insC		3_prime_UTR	Exon 16 of 16	ENSP00000264033.3
	CBL	ENST00000634840.1	TSL:5	c.*559_*560insC		3_prime_UTR	Exon 15 of 15	ENSP00000489324.1
	CBL	ENST00000634586.1	TSL:5	c.2575+705_2575+706insC		intron	N/A	ENSP00000489218.1

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36901 AN: 151814 Hom.: 4637 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.224

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.246

GnomAD4 exome AF: 0.267 AC: 69081 AN: 258754 Hom.: 9607 Cov.: 0 AF XY: 0.266 AC XY: 34920 AN XY: 131480

African (AFR) AF: 0.211 AC: 1537 AN: 7286

American (AMR) AF: 0.184 AC: 1857 AN: 10104

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 3188 AN: 9352

East Asian (EAS) AF: 0.386 AC: 9090 AN: 23558

South Asian (SAS) AF: 0.152 AC: 647 AN: 4260

European-Finnish (FIN) AF: 0.252 AC: 5390 AN: 21382

Middle Eastern (MID) AF: 0.273 AC: 360 AN: 1318

European-Non Finnish (NFE) AF: 0.259 AC: 42601 AN: 164668

Other (OTH) AF: 0.262 AC: 4411 AN: 16826

GnomAD4 genome AF: 0.243 AC: 36925 AN: 151932 Hom.: 4644 Cov.: 32 AF XY: 0.243 AC XY: 18048 AN XY: 74240

African (AFR) AF: 0.209 AC: 8645 AN: 41462

American (AMR) AF: 0.200 AC: 3059 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1156 AN: 3468

East Asian (EAS) AF: 0.386 AC: 1983 AN: 5142

South Asian (SAS) AF: 0.166 AC: 800 AN: 4818

European-Finnish (FIN) AF: 0.271 AC: 2856 AN: 10542

Middle Eastern (MID) AF: 0.228 AC: 66 AN: 290

European-Non Finnish (NFE) AF: 0.260 AC: 17632 AN: 67902

Other (OTH) AF: 0.248 AC: 524 AN: 2114

Alfa AF: 0.0692 Hom.: 137

Asia WGS AF: 0.277 AC: 966 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jul 29, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Noonan syndrome and Noonan-related syndrome Benign:1

Jan 20, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0070
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3833768; hg19: chr11-119171050; COSMIC: COSV50631555;