rs6589722

Variant names:

• chr11-119215073-C-A
• rs6589722
• NM_005188.4:c.195+8461C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-119215073-C-A
• chr11-119215073-C-G
• chr11-119215073-C-T

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+8461C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 151,666 control chromosomes in the GnomAD database, including 26,833 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 0.59 (26833 hom., cov: 30)
• Consequence: CBL NM_005188.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.365
• 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 = 0.858 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBL	NM_005188.4	c.195+8461C>A		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+8461C>A		intron_variant	Intron 1 of 15	1	NM_005188.4	ENSP00000264033.3

Frequencies

GnomAD3 genomes AF: 0.586 AC: 88756 AN: 151548 Hom.: 26803 Cov.: 30

Gnomad AFR AF: 0.669

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.879

Gnomad SAS AF: 0.752

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.532

Gnomad OTH AF: 0.574

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

GnomAD4 genome AF: 0.586 AC: 88833 AN: 151666 Hom.: 26833 Cov.: 30 AF XY: 0.591 AC XY: 43776 AN XY: 74104

African (AFR) AF: 0.669 AC: 27655 AN: 41322

American (AMR) AF: 0.450 AC: 6833 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 2221 AN: 3472

East Asian (EAS) AF: 0.879 AC: 4548 AN: 5172

South Asian (SAS) AF: 0.751 AC: 3620 AN: 4818

European-Finnish (FIN) AF: 0.571 AC: 6000 AN: 10508

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.533 AC: 36145 AN: 67876

Other (OTH) AF: 0.576 AC: 1209 AN: 2098

Alfa AF: 0.557 Hom.: 54893

Bravo AF: 0.580

Asia WGS AF: 0.786 AC: 2733 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.91
DANN	Benign	0.49
PhyloP100		-0.36
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: rs6589722; hg19: chr11-119085783;