11-119206302-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 703 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBL	NM_005188.4			upstream_gene_variant		ENST00000264033.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBL	ENST00000634586.1	c.-116C>T		5_prime_UTR_variant	1/18	5
CBL	ENST00000634840.1	c.-116C>T		5_prime_UTR_variant	1/15	5		A2
CBL	ENST00000264033.6			upstream_gene_variant		1	NM_005188.4	P2
CBL	ENST00000700472.1			upstream_gene_variant

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

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.00171

Gnomad4 ASJ exome AF: 0.000233

Gnomad4 EAS exome AF: 0.000120

Gnomad4 SAS exome AF: 0.000462

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.00135

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

Gnomad4 AFR AF: 0.0157

Gnomad4 AMR AF: 0.00269

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000395

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000893

Gnomad4 OTH AF: 0.00476

Alfa AF: 0.00413 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	16
Dann	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

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: rs550548107; hg19: chr11-119077012;