rs17280845

Variant names:

• chr3-105725692-C-T
• rs17280845
• NM_170662.5:c.1204-5442G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_170662.5(CBLB):​c.1204-5442G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 151,982 control chromosomes in the GnomAD database, including 3,826 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (3826 hom., cov: 32)
• Consequence: CBLB NM_170662.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• Publications: 7 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLB	NM_170662.5	c.1204-5442G>A		intron_variant	Intron 9 of 18	ENST00000394030.8	NP_733762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBLB	ENST00000394030.8	c.1204-5442G>A		intron_variant	Intron 9 of 18	1	NM_170662.5	ENSP00000377598.4

Frequencies

GnomAD3 genomes AF: 0.211 AC: 31992 AN: 151864 Hom.: 3833 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.0865

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.233

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.210 AC: 31983 AN: 151982 Hom.: 3826 Cov.: 32 AF XY: 0.205 AC XY: 15246 AN XY: 74254

African (AFR) AF: 0.110 AC: 4569 AN: 41462

American (AMR) AF: 0.193 AC: 2949 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 1001 AN: 3470

East Asian (EAS) AF: 0.0871 AC: 450 AN: 5168

South Asian (SAS) AF: 0.161 AC: 778 AN: 4822

European-Finnish (FIN) AF: 0.233 AC: 2447 AN: 10506

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.279 AC: 18933 AN: 67980

Other (OTH) AF: 0.230 AC: 485 AN: 2108

Alfa AF: 0.253 Hom.: 15373

Bravo AF: 0.204

Asia WGS AF: 0.113 AC: 396 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.70
DANN	Benign	0.74
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17280845; hg19: chr3-105444536;