11-119226075-T-G

Variant names:

• chr11-119226075-T-G
• rs12786104
• NM_005188.4:c.196-6373T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005188.4(CBL):​c.196-6373T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 152,126 control chromosomes in the GnomAD database, including 6,112 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (6112 hom., cov: 32)
• Consequence: CBL NM_005188.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.299
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBL	NM_005188.4	c.196-6373T>G		intron_variant	Intron 1 of 15	ENST00000264033.6	NP_005179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6	c.196-6373T>G		intron_variant	Intron 1 of 15	1	NM_005188.4	ENSP00000264033.3

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41266 AN: 152008 Hom.: 6115 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.276

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.271 AC: 41269 AN: 152126 Hom.: 6112 Cov.: 32 AF XY: 0.277 AC XY: 20587 AN XY: 74356

African (AFR) AF: 0.210 AC: 8736 AN: 41522

American (AMR) AF: 0.214 AC: 3275 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1077 AN: 3468

East Asian (EAS) AF: 0.485 AC: 2503 AN: 5166

South Asian (SAS) AF: 0.589 AC: 2843 AN: 4826

European-Finnish (FIN) AF: 0.302 AC: 3197 AN: 10582

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.276 AC: 18736 AN: 67980

Other (OTH) AF: 0.277 AC: 583 AN: 2102

Alfa AF: 0.258 Hom.: 840

Bravo AF: 0.257

Asia WGS AF: 0.487 AC: 1692 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.3
DANN	Benign	0.47
PhyloP100		0.30
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: rs12786104; hg19: chr11-119096785;