11-119206442-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005188.4(CBL):ā€‹c.25T>Cā€‹(p.Ser9Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 1,425,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S9F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000028 ( 0 hom. )

Consequence

CBL
NM_005188.4 missense

Scores

2
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.263
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.21600324).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CBLNM_005188.4 linkuse as main transcriptc.25T>C p.Ser9Pro missense_variant 1/16 ENST00000264033.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CBLENST00000264033.6 linkuse as main transcriptc.25T>C p.Ser9Pro missense_variant 1/161 NM_005188.4 P2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000104
AC:
2
AN:
192646
Hom.:
0
AF XY:
0.00000950
AC XY:
1
AN XY:
105310
show subpopulations
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:
0.0000233
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000281
AC:
4
AN:
1425924
Hom.:
0
Cov.:
32
AF XY:
0.00000141
AC XY:
1
AN XY:
706728
show subpopulations
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:
0.0000121
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000273
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 30, 2021In 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 affected with CBL-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with proline at codon 9 of the CBL protein (p.Ser9Pro). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and proline. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.037
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
22
DANN
Benign
0.95
DEOGEN2
Benign
0.31
T;.;T;.
Eigen
Benign
-0.54
Eigen_PC
Benign
-0.41
FATHMM_MKL
Benign
0.22
N
LIST_S2
Benign
0.69
T;T;T;T
M_CAP
Pathogenic
0.86
D
MetaRNN
Benign
0.22
T;T;T;T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
0.0
N;.;.;.
MutationTaster
Benign
0.95
N
PrimateAI
Pathogenic
0.90
D
PROVEAN
Benign
-0.38
N;.;.;.
REVEL
Uncertain
0.39
Sift
Uncertain
0.0070
D;.;.;.
Sift4G
Benign
0.12
T;T;T;.
Polyphen
0.0
B;.;.;.
Vest4
0.21
MutPred
0.20
Loss of phosphorylation at S9 (P = 0.0068);Loss of phosphorylation at S9 (P = 0.0068);Loss of phosphorylation at S9 (P = 0.0068);.;
MVP
0.83
MPC
1.9
ClinPred
0.27
T
GERP RS
0.84
Varity_R
0.22
gMVP
0.23

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1170501749; hg19: chr11-119077152; API