rs116474782

Variant names:

• chr3-105720150-C-T
• rs116474782
• NM_170662.5:c.1304G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001321786.1(CBLB):​c.1388G>A​(p.Cys463Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CBLB NM_001321786.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 5.39
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40167996).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321786.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLB	NM_170662.5	MANE Select	c.1304G>A	p.Cys435Tyr	missense	Exon 10 of 19	NP_733762.2
	CBLB	NM_001321786.1		c.1388G>A	p.Cys463Tyr	missense	Exon 10 of 19	NP_001308715.1
	CBLB	NM_001321788.2		c.1304G>A	p.Cys435Tyr	missense	Exon 10 of 19	NP_001308717.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLB	ENST00000394030.8	TSL:1 MANE Select	c.1304G>A	p.Cys435Tyr	missense	Exon 10 of 19	ENSP00000377598.4
	CBLB	ENST00000954009.1		c.1388G>A	p.Cys463Tyr	missense	Exon 11 of 20	ENSP00000624068.1
	CBLB	ENST00000954008.1		c.1304G>A	p.Cys435Tyr	missense	Exon 10 of 20	ENSP00000624067.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152156 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251172 AF XY: 0.00

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461558 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727086

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.0000671 AC: 3 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111762

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152274 Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 8 AN XY: 74454

African (AFR) AF: 0.000241 AC: 10 AN: 41542

American (AMR) AF: 0.000262 AC: 4 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000634 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.4
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.48
Sift	Benign	0.11	T
Sift4G	Benign	1.0	T
Polyphen		0.99	D
Vest4		0.69
MVP		0.91
MPC		1.1
ClinPred		0.20	T
GERP RS		6.0
Varity_R		0.14
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs116474782; hg19: chr3-105438994;