3-105863468-G-T

Variant names:

• chr3-105863468-G-T
• rs10511246
• NM_170662.5:c.168+3942C>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.168+3942C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 152,086 control chromosomes in the GnomAD database, including 3,577 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 (3577 hom., cov: 32)
• Consequence: CBLB NM_170662.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.731
• Publications: 5 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 (EAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLB	NM_170662.5	c.168+3942C>A		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+3942C>A		intron_variant	Intron 2 of 18	1	NM_170662.5	ENSP00000377598.4

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32028 AN: 151968 Hom.: 3568 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.202

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

GnomAD4 genome AF: 0.211 AC: 32057 AN: 152086 Hom.: 3577 Cov.: 32 AF XY: 0.213 AC XY: 15837 AN XY: 74372

African (AFR) AF: 0.225 AC: 9345 AN: 41476

American (AMR) AF: 0.229 AC: 3503 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 527 AN: 3470

East Asian (EAS) AF: 0.421 AC: 2174 AN: 5160

South Asian (SAS) AF: 0.232 AC: 1118 AN: 4828

European-Finnish (FIN) AF: 0.176 AC: 1861 AN: 10572

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12841 AN: 67970

Other (OTH) AF: 0.202 AC: 427 AN: 2116

Alfa AF: 0.131 Hom.: 274

Bravo AF: 0.219

Asia WGS AF: 0.314 AC: 1091 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.42
DANN	Benign	0.44
PhyloP100		-0.73
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: rs10511246; hg19: chr3-105582312;