chr3-105702188-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_170662.5(CBLB):c.1865G>C(p.Ser622Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00653 in 1,614,136 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 4 hom., cov: 30)

Exomes 𝑓: 0.0067 ( 64 hom. )

Consequence

CBLB
NM_170662.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 0.588

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0064592063).

BP6

Variant 3-105702188-C-G is Benign according to our data. Variant chr3-105702188-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 133823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLB	NM_170662.5 link	c.1865G>C	p.Ser622Thr	missense_variant	Exon 12 of 19	ENST00000394030.8	NP_733762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBLB	ENST00000394030.8 link	c.1865G>C	p.Ser622Thr	missense_variant	Exon 12 of 19	1	NM_170662.5	ENSP00000377598.4		Q13191-1

Frequencies

GnomAD3 genomes

AF:

0.00459

AC:

698

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00641

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00723

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00583

AC:

1464

AN:

251188

Hom.:

AF XY:

0.00603

AC XY:

818

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.00894

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00454

Gnomad FIN exome

AF:

0.00855

Gnomad NFE exome

AF:

0.00823

Gnomad OTH exome

AF:

0.00637

GnomAD4 exome

AF:

0.00673

AC:

9838

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00683

AC XY:

4968

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.00165

Gnomad4 ASJ exome

AF:

0.00834

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00530

Gnomad4 FIN exome

AF:

0.00914

Gnomad4 NFE exome

AF:

0.00730

Gnomad4 OTH exome

AF:

0.00631

GnomAD4 genome

AF:

0.00458

AC:

697

AN:

152256

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

341

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.00641

Gnomad4 NFE

AF:

0.00723

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00619

Hom.:

Bravo

AF:

0.00443

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00733

AC:

ExAC

AF:

0.00600

AC:

728

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00807

EpiControl

AF:

0.00901

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 27, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CBLB: BP4, BS2 -

CBLB-related disorder

Benign:1

Feb 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.25

T;T;.;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.72

.;T;T;T

MetaRNN

Benign

0.0065

T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.4

L;L;L;L

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.29

.;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.41

.;T;.;T

Sift4G

Benign

0.34

.;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.084, 0.12, 0.080

MVP

0.45

MPC

0.047

ClinPred

0.0012

GERP RS

3.8

Varity_R

0.033

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

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