11-119206449-C-A

Position:

• chr11-119206449-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005188.4(CBL):​c.32C>A​(p.Ala11Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000007 in 1,427,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. A11G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: CBL NM_005188.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.616

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19004405).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBL	NM_005188.4	c.32C>A	p.Ala11Asp	missense_variant	1/16	ENST00000264033.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBL	ENST00000264033.6	c.32C>A	p.Ala11Asp	missense_variant	1/16	1	NM_005188.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000513 AC: 1 AN: 194822 Hom.: 0 AF XY: 0.00000940 AC XY: 1 AN XY: 106334

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: 0.0000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000700 AC: 10 AN: 1427886 Hom.: 0 Cov.: 32 AF XY: 0.00000706 AC XY: 5 AN XY: 707796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000909

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Invitae

Oct 31, 2022

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 11 of the CBL protein (p.Ala11Asp). This variant has not been reported in the literature in individuals affected with CBL-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T;.;T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.0	N;.;.;.
MutationTaster	Benign	0.90	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.80	N;.;.;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.029	D;.;.;.
Sift4G	Benign	0.12	T;T;T;.
Polyphen		0.093	B;.;.;.
Vest4		0.49
MutPred		0.17		Gain of ubiquitination at K6 (P = 0.0204);Gain of ubiquitination at K6 (P = 0.0204);Gain of ubiquitination at K6 (P = 0.0204);.;
MVP		0.80
MPC		1.3
ClinPred		0.081	T
GERP RS		2.4
Varity_R		0.29
gMVP		0.50

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: rs1302101624; hg19: chr11-119077159;