Genetic Variant NM_170662.5:c.2702C>G (chr3-105659217-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_170662.5(CBLB):c.2702C>G(p.Ala901Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000337 in 1,613,840 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 2 hom. )

Consequence

CBLB
NM_170662.5 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 8.66

Publications

7 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08386779).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLB	NM_170662.5 link	c.2702C>G	p.Ala901Gly	missense_variant	Exon 19 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.2702C>G	p.Ala901Gly	missense_variant	Exon 19 of 19	1	NM_170662.5	ENSP00000377598.4		Q13191-1

Frequencies

GnomAD3 genomes

AF:

0.000440

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000518

AC:

130

AN:

250998

AF XY:

0.000472

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.000520

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000327

AC:

478

AN:

1461582

Hom.:

Cov.:

AF XY:

0.000340

AC XY:

247

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33466

American (AMR)

AF:

0.00110

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00107

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000229

AC:

255

AN:

1111782

Other (OTH)

AF:

0.000646

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000433

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41552

American (AMR)

AF:

0.000523

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000647

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000637

Hom.:

Bravo

AF:

0.000363

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000585

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000652

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

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

Uncertain

0.39

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;D

Eigen

Uncertain

0.60

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.084

T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

8.7

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.89

.;N

REVEL

Uncertain

0.45

Sift

Benign

0.11

.;T

Sift4G

Uncertain

0.042

.;D

Polyphen

1.0

D;D

Vest4

0.49

MVP

0.75

MPC

0.33

ClinPred

0.059

GERP RS

5.7

Varity_R

0.13

Mutation Taster

=76/24

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over