rs587778163

Variant names:

• chr3-105702190-C-CGCT
• rs587778163
• NM_170662.5:c.1860_1862dupAGC

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_170662.5(CBLB):​c.1860_1862dupAGC​(p.Ala621dup) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. A621A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: CBLB NM_170662.5 disruptive_inframe_insertion
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 5.40
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_170662.5. Strenght limited to Supporting due to length of the change: 1aa.

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.1860_1862dupAGC	p.Ala621dup	disruptive_inframe_insertion	Exon 12 of 19	NP_733762.2	Q13191-1
	CBLB	NM_001321786.1		c.1944_1946dupAGC	p.Ala649dup	disruptive_inframe_insertion	Exon 12 of 19	NP_001308715.1
	CBLB	NM_001321788.2		c.1860_1862dupAGC	p.Ala621dup	disruptive_inframe_insertion	Exon 12 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.1860_1862dupAGC	p.Ala621dup	disruptive_inframe_insertion	Exon 12 of 19	ENSP00000377598.4	Q13191-1
	CBLB	ENST00000954009.1		c.1944_1946dupAGC	p.Ala649dup	disruptive_inframe_insertion	Exon 13 of 20	ENSP00000624068.1
	CBLB	ENST00000954008.1		c.1860_1862dupAGC	p.Ala621dup	disruptive_inframe_insertion	Exon 12 of 20	ENSP00000624067.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587778163;

hg19: chr3-105421034;