rs35835913

chr3-105670275-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_170662.5(CBLB):c.2647A>G(p.Asn883Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,613,210 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.018 (71 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (69 hom.)
• Consequence: CBLB NM_170662.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 3.51

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032329261).
• BP6: Variant 3-105670275-T-C is Benign according to our data. Variant chr3-105670275-T-C is described in ClinVar as [Benign]. Clinvar id is 133825.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBLB	NM_170662.5	c.2647A>G	p.Asn883Asp	missense_variant	18/19	ENST00000394030.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBLB	ENST00000394030.8	c.2647A>G	p.Asn883Asp	missense_variant	18/19	1	NM_170662.5	P1

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2662 AN: 152108 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.0604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00464 AC: 1161 AN: 250462 Hom.: 35 AF XY: 0.00348 AC XY: 471 AN XY: 135334

Gnomad AFR exome AF: 0.0619

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00182 AC: 2657 AN: 1460984 Hom.: 69 Cov.: 29 AF XY: 0.00160 AC XY: 1164 AN XY: 726850

Gnomad4 AFR exome AF: 0.0630

Gnomad4 AMR exome AF: 0.00441

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000702

Gnomad4 OTH exome AF: 0.00391

GnomAD4 genome AF: 0.0175 AC: 2669 AN: 152226 Hom.: 71 Cov.: 32 AF XY: 0.0169 AC XY: 1257 AN XY: 74428

Gnomad4 AFR AF: 0.0604

Gnomad4 AMR AF: 0.00779

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00324 Hom.: 17

Bravo AF: 0.0201

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0595 AC: 262

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00559 AC: 679

Asia WGS AF: 0.00376 AC: 14 AN: 3476

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

CBLB-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2020

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). -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.38	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.81	D;N;N
PrimateAI	Benign	0.47	T
REVEL	Uncertain	0.31
Polyphen		0.094	B;B
Vest4		0.38
MVP		0.83
MPC		0.057
ClinPred		0.016	T
GERP RS		4.5
Varity_R		0.082

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

Other links and lift over

dbSNP: rs35835913; hg19: chr3-105389119;