rs41302192

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 16/20 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

Publications

19 publications found

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 Gene-Disease associations (from GenCC):

autoimmune disease, multisystem, infantile-onset, 3
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

CBLB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 133823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170662.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CBLB	NM_170662.5	MANE Select	c.1865G>C	p.Ser622Thr	missense	Exon 12 of 19	NP_733762.2	Q13191-1
CBLB	NM_001321786.1		c.1949G>C	p.Ser650Thr	missense	Exon 12 of 19	NP_001308715.1
CBLB	NM_001321788.2		c.1865G>C	p.Ser622Thr	missense	Exon 12 of 19	NP_001308717.1	Q13191-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CBLB	ENST00000394030.8	TSL:1 MANE Select	c.1865G>C	p.Ser622Thr	missense	Exon 12 of 19	ENSP00000377598.4	Q13191-1
CBLB	ENST00000954009.1		c.1949G>C	p.Ser650Thr	missense	Exon 13 of 20	ENSP00000624068.1
CBLB	ENST00000954008.1		c.1865G>C	p.Ser622Thr	missense	Exon 12 of 20	ENSP00000624067.1

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

GnomAD2 exomes

AF:

0.00583

AC:

1464

AN:

251188

AF XY:

0.00603

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 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

African (AFR)

AF:

0.00116

AC:

AN:

33480

American (AMR)

AF:

0.00165

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00834

AC:

218

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00530

AC:

457

AN:

86256

European-Finnish (FIN)

AF:

0.00914

AC:

488

AN:

53420

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00730

AC:

8121

AN:

1112002

Other (OTH)

AF:

0.00631

AC:

381

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

589

1178

1767

2356

2945

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

286

572

858

1144

1430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00458

AC:

697

AN:

152256

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

341

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41534

American (AMR)

AF:

0.00183

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00477

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00641

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00723

AC:

492

AN:

68018

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

CBLB-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.25

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0065

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.4

PhyloP100

0.59

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.29

REVEL

Benign

0.18

Sift

Benign

0.41

Sift4G

Benign

0.34

Polyphen

0.0

Vest4

0.084

MVP

0.45

MPC

0.047

ClinPred

0.0012

GERP RS

3.8

Varity_R

0.033

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over