Genetic Variant NM_170662.5:c.1863G>A (chr3-105702190-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_170662.5(CBLB):c.1863G>A(p.Ala621Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,614,090 control chromosomes in the GnomAD database, including 1,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.022 ( 87 hom., cov: 30)

Exomes 𝑓: 0.030 ( 1088 hom. )

Consequence

CBLB
NM_170662.5 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -2.17

Publications

16 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 3-105702190-C-T is Benign according to our data. Variant chr3-105702190-C-T is described in ClinVar as [Benign]. Clinvar id is 3060876.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-2.17 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLB	NM_170662.5 link	c.1863G>A	p.Ala621Ala	synonymous_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.1863G>A	p.Ala621Ala	synonymous_variant	Exon 12 of 19	1	NM_170662.5	ENSP00000377598.4		Q13191-1

Frequencies

GnomAD3 genomes

AF:

0.0223

AC:

3397

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00471

Gnomad AMI

AF:

0.0802

Gnomad AMR

AF:

0.0213

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.121

Gnomad SAS

AF:

0.0634

Gnomad FIN

AF:

0.00500

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0248

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.0312

AC:

7833

AN:

251182

AF XY:

0.0329

show subpopulations

Gnomad AFR exome

AF:

0.00388

Gnomad AMR exome

AF:

0.00801

Gnomad ASJ exome

AF:

0.0172

Gnomad EAS exome

AF:

0.120

Gnomad FIN exome

AF:

0.00577

Gnomad NFE exome

AF:

0.0239

Gnomad OTH exome

AF:

0.0330

GnomAD4 exome

AF:

0.0299

AC:

43691

AN:

1461860

Hom.:

1088

Cov.:

AF XY:

0.0310

AC XY:

22558

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00385

AC:

129

AN:

33480

American (AMR)

AF:

0.00937

AC:

419

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0178

AC:

464

AN:

26134

East Asian (EAS)

AF:

0.135

AC:

5352

AN:

39698

South Asian (SAS)

AF:

0.0675

AC:

5821

AN:

86256

European-Finnish (FIN)

AF:

0.00592

AC:

316

AN:

53418

Middle Eastern (MID)

AF:

0.0298

AC:

172

AN:

5768

European-Non Finnish (NFE)

AF:

0.0261

AC:

29013

AN:

1111986

Other (OTH)

AF:

0.0332

AC:

2005

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

2587

5173

7760

10346

12933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0223

AC:

3397

AN:

152230

Hom.:

Cov.:

AF XY:

0.0223

AC XY:

1663

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00470

AC:

195

AN:

41530

American (AMR)

AF:

0.0212

AC:

325

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

AN:

3472

East Asian (EAS)

AF:

0.121

AC:

626

AN:

5174

South Asian (SAS)

AF:

0.0641

AC:

309

AN:

4824

European-Finnish (FIN)

AF:

0.00500

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0247

AC:

1683

AN:

68010

Other (OTH)

AF:

0.0270

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

170

339

509

678

848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0222

Hom.:

104

Bravo

AF:

0.0231

Asia WGS

AF:

0.107

AC:

372

AN:

3478

EpiCase

AF:

0.0251

EpiControl

AF:

0.0235

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CBLB-related disorder

Benign:1

May 28, 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

-0.75

CADD

Benign

0.22

(source)

DANN

Benign

0.46

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism (auto)

(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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NM_170662.5:c.1863G>A

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