rs11217184

Variant names:

• chr11-119208283-A-G
• rs11217184
• NM_005188.4:c.195+1671A>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.195+1671A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 152,134 control chromosomes in the GnomAD database, including 4,383 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 0.23 (4383 hom., cov: 32)
• Consequence: CBL NM_005188.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.567
• Publications: 7 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBL	NM_005188.4	c.195+1671A>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.195+1671A>G		intron_variant	Intron 1 of 15	1	NM_005188.4	ENSP00000264033.3

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35455 AN: 152016 Hom.: 4377 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.240

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

GnomAD4 genome AF: 0.233 AC: 35480 AN: 152134 Hom.: 4383 Cov.: 32 AF XY: 0.234 AC XY: 17405 AN XY: 74368

African (AFR) AF: 0.180 AC: 7482 AN: 41508

American (AMR) AF: 0.198 AC: 3026 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1142 AN: 3468

East Asian (EAS) AF: 0.385 AC: 1989 AN: 5168

South Asian (SAS) AF: 0.165 AC: 795 AN: 4828

European-Finnish (FIN) AF: 0.269 AC: 2841 AN: 10572

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17419 AN: 67988

Other (OTH) AF: 0.242 AC: 512 AN: 2116

Alfa AF: 0.240 Hom.: 595

Bravo AF: 0.229

Asia WGS AF: 0.276 AC: 964 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.5
DANN	Benign	0.53
PhyloP100		0.57
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: rs11217184; hg19: chr11-119078993;