rs2511837

Positions:

• chr11-119308297-T-C
• chr11-119308297-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000637974.1(CBL):​c.2522-5121T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 153,534 control chromosomes in the GnomAD database, including 27,800 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 0.58 (27593 hom., cov: 31)
  • Exomes 𝑓: 0.49 (207 hom.)
• Consequence: CBL ENST00000637974.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.92

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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000637974.1	c.2522-5121T>C		intron_variant		5		ENSP00000490763
CBL	ENST00000700472.1	c.*1980-5121T>C		intron_variant, NMD_transcript_variant				ENSP00000515005

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87610 AN: 151868 Hom.: 27564 Cov.: 31

Gnomad AFR AF: 0.833

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.726

Gnomad SAS AF: 0.657

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.569

GnomAD4 exome AF: 0.491 AC: 760 AN: 1548 Hom.: 207 AF XY: 0.504 AC XY: 367 AN XY: 728

Gnomad4 AFR exome AF: 0.917

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.531

Gnomad4 EAS exome AF: 0.738

Gnomad4 SAS exome AF: 0.600

Gnomad4 FIN exome AF: 0.353

Gnomad4 NFE exome AF: 0.440

Gnomad4 OTH exome AF: 0.509

GnomAD4 genome AF: 0.577 AC: 87691 AN: 151986 Hom.: 27593 Cov.: 31 AF XY: 0.579 AC XY: 43002 AN XY: 74282

Gnomad4 AFR AF: 0.832

Gnomad4 AMR AF: 0.450

Gnomad4 ASJ AF: 0.589

Gnomad4 EAS AF: 0.726

Gnomad4 SAS AF: 0.656

Gnomad4 FIN AF: 0.431

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.573

Alfa AF: 0.485 Hom.: 15435

Bravo AF: 0.588

Asia WGS AF: 0.677 AC: 2352 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.034
DANN	Benign	0.57

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2511837; hg19: chr11-119179007;