rs3772534

Variant names:

• chr3-105702190-C-T
• rs3772534
• NM_170662.5:c.1863G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_170662.5(CBLB):​c.1863G>A​(p.Ala621Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,614,090 control chromosomes in the GnomAD database, including 1,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.022 (87 hom., cov: 30)
  • Exomes 𝑓: 0.030 (1088 hom.)
• Consequence: CBLB NM_170662.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.17
• Publications: 16 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-105702190-C-T is Benign according to our data. Variant chr3-105702190-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060876.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-2.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLB	NM_170662.5	MANE Select	c.1863G>A	p.Ala621Ala	synonymous	Exon 12 of 19	NP_733762.2
	CBLB	NM_001321786.1		c.1947G>A	p.Ala649Ala	synonymous	Exon 12 of 19	NP_001308715.1
	CBLB	NM_001321788.2		c.1863G>A	p.Ala621Ala	synonymous	Exon 12 of 19	NP_001308717.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLB	ENST00000394030.8	TSL:1 MANE Select	c.1863G>A	p.Ala621Ala	synonymous	Exon 12 of 19	ENSP00000377598.4
	CBLB	ENST00000405772.5	TSL:2	c.1863G>A	p.Ala621Ala	synonymous	Exon 12 of 16	ENSP00000384938.1
	CBLB	ENST00000403724.5	TSL:2	c.1863G>A	p.Ala621Ala	synonymous	Exon 12 of 15	ENSP00000384816.1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3397 AN: 152112 Hom.: 86 Cov.: 30

Gnomad AFR AF: 0.00471

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.0634

Gnomad FIN AF: 0.00500

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0248

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0312 AC: 7833 AN: 251182 AF XY: 0.0329

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.00801

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.00577

Gnomad NFE exome AF: 0.0239

Gnomad OTH exome AF: 0.0330

GnomAD4 exome AF: 0.0299 AC: 43691 AN: 1461860 Hom.: 1088 Cov.: 34 AF XY: 0.0310 AC XY: 22558 AN XY: 727228

African (AFR) AF: 0.00385 AC: 129 AN: 33480

American (AMR) AF: 0.00937 AC: 419 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0178 AC: 464 AN: 26134

East Asian (EAS) AF: 0.135 AC: 5352 AN: 39698

South Asian (SAS) AF: 0.0675 AC: 5821 AN: 86256

European-Finnish (FIN) AF: 0.00592 AC: 316 AN: 53418

Middle Eastern (MID) AF: 0.0298 AC: 172 AN: 5768

European-Non Finnish (NFE) AF: 0.0261 AC: 29013 AN: 1111986

Other (OTH) AF: 0.0332 AC: 2005 AN: 60396

GnomAD4 genome AF: 0.0223 AC: 3397 AN: 152230 Hom.: 87 Cov.: 30 AF XY: 0.0223 AC XY: 1663 AN XY: 74424

African (AFR) AF: 0.00470 AC: 195 AN: 41530

American (AMR) AF: 0.0212 AC: 325 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

East Asian (EAS) AF: 0.121 AC: 626 AN: 5174

South Asian (SAS) AF: 0.0641 AC: 309 AN: 4824

European-Finnish (FIN) AF: 0.00500 AC: 53 AN: 10600

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0247 AC: 1683 AN: 68010

Other (OTH) AF: 0.0270 AC: 57 AN: 2112

Alfa AF: 0.0222 Hom.: 104

Bravo AF: 0.0231

Asia WGS AF: 0.107 AC: 372 AN: 3478

EpiCase AF: 0.0251

EpiControl AF: 0.0235

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CBLB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.22
DANN	Benign	0.46
PhyloP100		-2.2
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: rs3772534; hg19: chr3-105421034; COSMIC: COSV51423510; COSMIC: COSV51423510;