dbSNP rs587777936: CBLB:p.Pro7Arg (chr3-105869369-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001321790.2(CBLB):c.20C>G(p.Pro7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,342,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

CBLB
NM_001321790.2 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 1.40

Publications

1 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:

ENSG00000288848 (HGNC:):

ENSG00000288848 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044833124).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
CBLB	NM_001321790.2 link	c.20C>G	p.Pro7Arg	missense_variant	Exon 1 of 18	NP_001308719.1
CBLB	XM_017007395.2 link	c.20C>G	p.Pro7Arg	missense_variant	Exon 1 of 19	XP_016862884.1
CBLB	XM_017007398.2 link	c.20C>G	p.Pro7Arg	missense_variant	Exon 1 of 18	XP_016862887.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
CBLB	ENST00000438603.6 link	c.20C>G	p.Pro7Arg	missense_variant	Exon 1 of 4	4	ENSP00000409750.2	C9JRB3
CBLB	ENST00000643322.1 link	n.20C>G		non_coding_transcript_exon_variant	Exon 1 of 21		ENSP00000496352.1	A0A2R8YFD4
ENSG00000288848	ENST00000690303.3 link	n.250G>C		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000226

AC:

AN:

146072

AF XY:

0.000178

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00308

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1190620

Hom.:

Cov.:

AF XY:

0.0000240

AC XY:

AN XY:

582822

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25882

American (AMR)

AF:

0.00

AC:

AN:

29242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18372

East Asian (EAS)

AF:

0.00195

AC:

AN:

20006

South Asian (SAS)

AF:

0.00

AC:

AN:

76546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4656

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

943734

Other (OTH)

AF:

0.00

AC:

AN:

44808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41576

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000966

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

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:

0.00

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.000195

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

Benign

0.083

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.21

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.25

M_CAP

Benign

0.029

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.76

PhyloP100

1.4

PROVEAN

Benign

-0.13

REVEL

Benign

0.19

Sift

Benign

0.14

MutPred

0.11

Gain of methylation at P7 (P = 0.0203);

MVP

0.19

ClinPred

0.094

GERP RS

2.4

PromoterAI

0.050

Neutral

(source)

Mutation Taster

=98/2

polymorphism

(source)

Splicing

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