Genetic Variant CBLB:p.Pro871Pro (chr3-105670309-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BA1

The NM_170662.5(CBLB):c.2613T>C(p.Pro871Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,609,800 control chromosomes in the GnomAD database, including 38,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.22 ( 3819 hom., cov: 32)

Exomes 𝑓: 0.21 ( 34672 hom. )

Consequence

CBLB
NM_170662.5 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.769

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 Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 3-105670309-A-G is Benign according to our data. Variant chr3-105670309-A-G is described in ClinVar as [Benign]. Clinvar id is 3056926.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=0.769 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLB	NM_170662.5 link	c.2613T>C	p.Pro871Pro	synonymous_variant	Exon 18 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.2613T>C	p.Pro871Pro	synonymous_variant	Exon 18 of 19	1	NM_170662.5	ENSP00000377598.4		Q13191-1

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

33517

AN:

151948

Hom.:

3812

Cov.:

show subpopulations

Gnomad AFR

AF:

0.223

Gnomad AMI

AF:

0.242

Gnomad AMR

AF:

0.257

Gnomad ASJ

AF:

0.142

Gnomad EAS

AF:

0.216

Gnomad SAS

AF:

0.145

Gnomad FIN

AF:

0.268

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.214

Gnomad OTH

AF:

0.193

GnomAD3 exomes

AF:

0.223

AC:

55670

AN:

249796

Hom.:

6655

AF XY:

0.216

AC XY:

29107

AN XY:

135046

show subpopulations

Gnomad AFR exome

AF:

0.221

Gnomad AMR exome

AF:

0.324

Gnomad ASJ exome

AF:

0.145

Gnomad EAS exome

AF:

0.214

Gnomad SAS exome

AF:

0.141

Gnomad FIN exome

AF:

0.273

Gnomad NFE exome

AF:

0.214

Gnomad OTH exome

AF:

0.208

GnomAD4 exome

AF:

0.215

AC:

312961

AN:

1457734

Hom.:

34672

Cov.:

AF XY:

0.212

AC XY:

153919

AN XY:

725430

show subpopulations

Gnomad4 AFR exome

AF:

0.229

Gnomad4 AMR exome

AF:

0.315

Gnomad4 ASJ exome

AF:

0.141

Gnomad4 EAS exome

AF:

0.220

Gnomad4 SAS exome

AF:

0.145

Gnomad4 FIN exome

AF:

0.271

Gnomad4 NFE exome

AF:

0.215

Gnomad4 OTH exome

AF:

0.211

GnomAD4 genome

AF:

0.221

AC:

33542

AN:

152066

Hom.:

3819

Cov.:

AF XY:

0.224

AC XY:

16630

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.223

Gnomad4 AMR

AF:

0.258

Gnomad4 ASJ

AF:

0.142

Gnomad4 EAS

AF:

0.216

Gnomad4 SAS

AF:

0.147

Gnomad4 FIN

AF:

0.268

Gnomad4 NFE

AF:

0.214

Gnomad4 OTH

AF:

0.193

Alfa

AF:

0.211

Hom.:

1575

Bravo

AF:

0.221

Asia WGS

AF:

0.158

AC:

548

AN:

3478

EpiCase

AF:

0.209

EpiControl

AF:

0.200

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CBLB-related disorder

Benign:1

Nov 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

3.5

DANN

Benign

0.72

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

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