11-119206302-C-T

Variant names:

• chr11-119206302-C-T
• rs550548107
• ENST00000634586.1:c.-116C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The ENST00000634586.1(CBL):​c.-116C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 830,164 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (3 hom.)
• Consequence: CBL ENST00000634586.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.952
• Publications: 1 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: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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=-0.35).
• BP6: Variant 11-119206302-C-T is Benign according to our data. Variant chr11-119206302-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1214031.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00468 (705/150554) while in subpopulation AFR AF = 0.0157 (643/41068). AF 95% confidence interval is 0.0147. There are 5 homozygotes in GnomAd4. There are 311 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 705 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000634586.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBL	NM_005188.4	MANE Select	c.-116C>T		upstream_gene	N/A	NP_005179.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBL	ENST00000634586.1	TSL:5	c.-116C>T		5_prime_UTR	Exon 1 of 18	ENSP00000489218.1	A0A0U1RQX8
	CBL	ENST00000634840.1	TSL:5	c.-116C>T		5_prime_UTR	Exon 1 of 15	ENSP00000489324.1	A0A0U1RR39
	CBL	ENST00000264033.6	TSL:1 MANE Select	c.-116C>T		upstream_gene	N/A	ENSP00000264033.3	P22681

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 703 AN: 150446 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00270

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000893

Gnomad OTH AF: 0.00481

GnomAD4 exome AF: 0.000459 AC: 312 AN: 679610 Hom.: 3 Cov.: 9 AF XY: 0.000394 AC XY: 136 AN XY: 345074

African (AFR) AF: 0.0134 AC: 177 AN: 13256

American (AMR) AF: 0.00171 AC: 16 AN: 9382

Ashkenazi Jewish (ASJ) AF: 0.000233 AC: 3 AN: 12878

East Asian (EAS) AF: 0.000120 AC: 3 AN: 25098

South Asian (SAS) AF: 0.000462 AC: 15 AN: 32476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26458

Middle Eastern (MID) AF: 0.000430 AC: 1 AN: 2328

European-Non Finnish (NFE) AF: 0.000103 AC: 54 AN: 525796

Other (OTH) AF: 0.00135 AC: 43 AN: 31938

GnomAD4 genome AF: 0.00468 AC: 705 AN: 150554 Hom.: 5 Cov.: 32 AF XY: 0.00423 AC XY: 311 AN XY: 73608

African (AFR) AF: 0.0157 AC: 643 AN: 41068

American (AMR) AF: 0.00269 AC: 41 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3362

East Asian (EAS) AF: 0.000395 AC: 2 AN: 5066

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000893 AC: 6 AN: 67218

Other (OTH) AF: 0.00476 AC: 10 AN: 2100

Alfa AF: 0.00413 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Uncertain	0.98
PhyloP100		0.95
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=300/0	polymorphism

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: rs550548107; hg19: chr11-119077012;