3-105670309-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_170662.5(CBLB):c.2613T>C(p.Pro871=) 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 (★).

• Frequency:
  • Genomes: 𝑓 0.22 (3819 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34672 hom.)
• Consequence: CBLB NM_170662.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.769

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 -13 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 criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
CBLB	NM_170662.5	c.2613T>C	p.Pro871=	synonymous_variant	18/19	ENST00000394030.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBLB	ENST00000394030.8	c.2613T>C	p.Pro871=	synonymous_variant	18/19	1	NM_170662.5	P1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33517 AN: 151948 Hom.: 3812 Cov.: 32

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

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.: 29 AF XY: 0.212 AC XY: 153919 AN XY: 725430

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.: 32 AF XY: 0.224 AC XY: 16630 AN XY: 74332

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: criteria provided, single submitter

Submissions by phenotype

CBLB-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

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

Other links and lift over

dbSNP: rs11713094; hg19: chr3-105389153; COSMIC: COSV51421203;