rs9846534

Variant names:

• chr3-105862906-T-C
• rs9846534
• NM_170662.5:c.168+4504A>G

Variant summary

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

The NM_170662.5(CBLB):​c.168+4504A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,042 control chromosomes in the GnomAD database, including 3,696 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 (3696 hom., cov: 31)
• Consequence: CBLB NM_170662.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.708
• Publications: 6 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLB	NM_170662.5	c.168+4504A>G		intron_variant	Intron 2 of 18	ENST00000394030.8	NP_733762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBLB	ENST00000394030.8	c.168+4504A>G		intron_variant	Intron 2 of 18	1	NM_170662.5	ENSP00000377598.4

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32590 AN: 151922 Hom.: 3685 Cov.: 31

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.202

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

GnomAD4 genome AF: 0.215 AC: 32635 AN: 152042 Hom.: 3696 Cov.: 31 AF XY: 0.216 AC XY: 16071 AN XY: 74330

African (AFR) AF: 0.230 AC: 9551 AN: 41466

American (AMR) AF: 0.231 AC: 3520 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 538 AN: 3472

East Asian (EAS) AF: 0.420 AC: 2171 AN: 5164

South Asian (SAS) AF: 0.233 AC: 1125 AN: 4826

European-Finnish (FIN) AF: 0.176 AC: 1863 AN: 10584

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13179 AN: 67950

Other (OTH) AF: 0.202 AC: 426 AN: 2104

Alfa AF: 0.205 Hom.: 506

Bravo AF: 0.223

Asia WGS AF: 0.318 AC: 1106 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.55
PhyloP100		0.71
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: rs9846534; hg19: chr3-105581750;