chr3-105720058-T-C

Variant names:

• chr3-105720058-T-C
• rs61758360
• NM_170662.5:c.1396A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_170662.5(CBLB):​c.1396A>G​(p.Asn466Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,612 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: CBLB NM_170662.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 1.84
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003571868).
• BP6: Variant 3-105720058-T-C is Benign according to our data. Variant chr3-105720058-T-C is described in ClinVar as Benign. ClinVar VariationId is 133818.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00164 (250/152274) while in subpopulation EAS AF = 0.0453 (235/5186). AF 95% confidence interval is 0.0406. There are 3 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170662.5. 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.1396A>G	p.Asn466Asp	missense	Exon 10 of 19	NP_733762.2	Q13191-1
	CBLB	NM_001321786.1		c.1480A>G	p.Asn494Asp	missense	Exon 10 of 19	NP_001308715.1
	CBLB	NM_001321788.2		c.1396A>G	p.Asn466Asp	missense	Exon 10 of 19	NP_001308717.1	Q13191-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLB	ENST00000394030.8	TSL:1 MANE Select	c.1396A>G	p.Asn466Asp	missense	Exon 10 of 19	ENSP00000377598.4	Q13191-1
	CBLB	ENST00000954009.1		c.1480A>G	p.Asn494Asp	missense	Exon 11 of 20	ENSP00000624068.1
	CBLB	ENST00000954008.1		c.1396A>G	p.Asn466Asp	missense	Exon 10 of 20	ENSP00000624067.1

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152156 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0452

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00405 AC: 1017 AN: 251104 AF XY: 0.00367

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0539

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00107 AC: 1559 AN: 1461338 Hom.: 27 Cov.: 32 AF XY: 0.00102 AC XY: 742 AN XY: 727020

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.000112 AC: 5 AN: 44698

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

East Asian (EAS) AF: 0.0350 AC: 1389 AN: 39688

South Asian (SAS) AF: 0.000533 AC: 46 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111558

Other (OTH) AF: 0.00169 AC: 102 AN: 60372

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152274 Hom.: 3 Cov.: 31 AF XY: 0.00177 AC XY: 132 AN XY: 74458

African (AFR) AF: 0.0000722 AC: 3 AN: 41558

American (AMR) AF: 0.000196 AC: 3 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0453 AC: 235 AN: 5186

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00214 Hom.: 10

Bravo AF: 0.00220

ExAC AF: 0.00400 AC: 486

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CBLB-related disorder (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.019
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.31	N
REVEL	Uncertain	0.32
Sift	Benign	0.043	D
Sift4G	Benign	0.66	T
Polyphen		0.061	B
Vest4		0.27
MVP		0.80
MPC		0.60
ClinPred		0.017	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066
Mutation Taster		=99/1	polymorphism

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: rs61758360; hg19: chr3-105438902; COSMIC: COSV51423525;