Variant 3-105685414-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_170662.5(CBLB):c.2107G>C(p.Glu703Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,534 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CBLB
NM_170662.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.43

Variant links:

Genes affected

CBLB (HGNC:1542): (Cbl proto-oncogene B) This gene encodes an E3 ubiquitin-protein ligase which promotes proteosome-mediated protein degradation by transferring ubiquitin from an E2 ubiquitin-conjugating enzyme to a substrate. The encoded protein is involved in the regulation of immune response by limiting T-cell receptor, B-cell receptor, and high affinity immunoglobulin epsilon receptor activation. Studies in mouse suggest that this gene is involved in antifungal host defense and that its inhibition leads to increased fungal killing. Manipulation of this gene may be beneficial in implementing immunotherapies for a variety of conditions, including cancer, autoimmune diseases, allergies, and infections. [provided by RefSeq, Sep 2017]

CBLB links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28523064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBLB	NM_170662.5 linkuse as main transcript	c.2107G>C	p.Glu703Gln	missense_variant	14/19	ENST00000394030.8	NP_733762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBLB	ENST00000394030.8 linkuse as main transcript	c.2107G>C	p.Glu703Gln	missense_variant	14/19	1	NM_170662.5	ENSP00000377598	P1	Q13191-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460534

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726648

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2023

The c.2107G>C (p.E703Q) alteration is located in exon 14 (coding exon 13) of the CBLB gene. This alteration results from a G to C substitution at nucleotide position 2107, causing the glutamic acid (E) at amino acid position 703 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.0027

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;T;.;.

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

.;T;T;T

M_CAP

Benign

0.057

MetaRNN

Benign

0.29

T;T;T;T

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

1.7

L;L;L;L

MutationTaster

Benign

0.70

D;D;D;D

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.82

.;N;N;N

REVEL

Uncertain

0.39

Sift

Uncertain

0.015

.;D;.;D

Sift4G

Benign

0.24

.;T;D;D

Polyphen

0.19

B;B;B;.

Vest4

0.22, 0.23, 0.22

MutPred

0.12

Gain of glycosylation at T698 (P = 0.1927);Gain of glycosylation at T698 (P = 0.1927);Gain of glycosylation at T698 (P = 0.1927);Gain of glycosylation at T698 (P = 0.1927);

MVP

0.70

MPC

0.074

ClinPred

0.86

GERP RS

5.3

Varity_R

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over