11-119285472-A-T

Variant names:

• chr11-119285472-A-T
• rs376094293
• NM_005188.4:c.1847A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005188.4(CBL):​c.1847A>T​(p.Asn616Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,102 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N616S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CBL NM_005188.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.49
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005188.4. 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.1847A>T	p.Asn616Ile	missense	Exon 11 of 16	NP_005179.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBL	ENST00000264033.6	TSL:1 MANE Select	c.1847A>T	p.Asn616Ile	missense	Exon 11 of 16	ENSP00000264033.3	P22681
	CBL	ENST00000634586.1	TSL:5	c.1847A>T	p.Asn616Ile	missense	Exon 11 of 18	ENSP00000489218.1	A0A0U1RQX8
	CBL	ENST00000637974.1	TSL:5	c.1841A>T	p.Asn614Ile	missense	Exon 11 of 17	ENSP00000490763.1	A0A1B0GW38

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74284

African (AFR) AF: 0.0000241 AC: 1 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	not provided (1)
-	1	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	-0.046	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.041	D
Polyphen		0.95	P
Vest4		0.89
MutPred		0.22		Loss of solvent accessibility (P = 0.0468)
MVP		0.94
MPC		0.53
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.52
gMVP		0.60
Mutation Taster		=19/81	disease causing

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: rs376094293; hg19: chr11-119156182;