11-119287872-A-T

Position:

• chr11-119287872-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005188.4(CBL):​c.1962A>T​(p.Leu654Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CBL NM_005188.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.340

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041197717).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBL	NM_005188.4	c.1962A>T	p.Leu654Phe	missense_variant	12/16	ENST00000264033.6	NP_005179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6	c.1962A>T	p.Leu654Phe	missense_variant	12/16	1	NM_005188.4	ENSP00000264033	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

RASopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 06, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CBL protein function. This variant has not been reported in the literature in individuals with CBL-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 654 of the CBL protein (p.Leu654Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.33	T;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.041	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.13	N;.;.;.
REVEL	Benign	0.12
Sift	Benign	0.20	T;.;.;.
Sift4G	Benign	0.72	T;T;T;.
Polyphen		0.0	B;.;.;.
Vest4		0.087
MutPred		0.11		Gain of glycosylation at S652 (P = 0.1858);Gain of glycosylation at S652 (P = 0.1858);.;.;
MVP		0.82
MPC		0.21
ClinPred		0.038	T
GERP RS		2.8
Varity_R		0.030
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-119158582;