rs769423231

Variant names:

• chr11-119287855-A-G
• rs769423231
• NM_005188.4:c.1945A>G

Variant summary

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

The NM_005188.4(CBL):​c.1945A>G​(p.Met649Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,220 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CBL NM_005188.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0410

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=0.039901525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBL	NM_005188.4	c.1945A>G	p.Met649Val	missense_variant	Exon 12 of 16	ENST00000264033.6	NP_005179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6	c.1945A>G	p.Met649Val	missense_variant	Exon 12 of 16	1	NM_005188.4	ENSP00000264033.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251460 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453220 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 723630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CBL-related disorder Uncertain:1

Sep 03, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy Uncertain:1

Jul 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 649 of the CBL protein (p.Met649Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 374799). 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 with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.7
DANN	Benign	0.60
DEOGEN2	Benign	0.37	T;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.38	T;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.040	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.28	N;.;.;.
REVEL	Benign	0.18
Sift	Benign	1.0	T;.;.;.
Sift4G	Benign	0.54	T;T;T;.
Polyphen		0.0	B;.;.;.
Vest4		0.054
MutPred		0.11		Loss of phosphorylation at S652 (P = 0.1543);Loss of phosphorylation at S652 (P = 0.1543);.;.;
MVP		0.65
MPC		0.20
ClinPred		0.026	T
GERP RS		-7.5
Varity_R		0.027
gMVP		0.17

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: rs769423231; hg19: chr11-119158565;