3-105869001-C-G

Variant names:

• chr3-105869001-C-G
• rs7649466
• NM_170662.5:c.-280G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_170662.5(CBLB):​c.-280G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,054,432 control chromosomes in the GnomAD database, including 16,831 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 0.19 (2663 hom., cov: 32)
  • Exomes 𝑓: 0.18 (14168 hom.)
• Consequence: CBLB NM_170662.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0320
• Publications: 13 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)

ENSG00000288848 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.291 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.-280G>C		5_prime_UTR	Exon 1 of 19	NP_733762.2
	CBLB	NR_135806.2		n.12G>C		non_coding_transcript_exon	Exon 1 of 21
	CBLB	NR_135807.2		n.12G>C		non_coding_transcript_exon	Exon 1 of 21

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLB	ENST00000394030.8	TSL:1 MANE Select	c.-280G>C		5_prime_UTR	Exon 1 of 19	ENSP00000377598.4
	CBLB	ENST00000645759.1		n.-104G>C		non_coding_transcript_exon	Exon 1 of 20	ENSP00000496297.1
	CBLB	ENST00000646825.1		n.-104G>C		non_coding_transcript_exon	Exon 1 of 20	ENSP00000496761.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 27974 AN: 150714 Hom.: 2655 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.0935

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.170

GnomAD4 exome AF: 0.177 AC: 159886 AN: 903592 Hom.: 14168 Cov.: 30 AF XY: 0.177 AC XY: 75057 AN XY: 424126

African (AFR) AF: 0.200 AC: 3218 AN: 16058

American (AMR) AF: 0.206 AC: 462 AN: 2244

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 836 AN: 6508

East Asian (EAS) AF: 0.317 AC: 1300 AN: 4106

South Asian (SAS) AF: 0.173 AC: 5513 AN: 31866

European-Finnish (FIN) AF: 0.158 AC: 665 AN: 4222

Middle Eastern (MID) AF: 0.143 AC: 272 AN: 1896

European-Non Finnish (NFE) AF: 0.176 AC: 142027 AN: 805710

Other (OTH) AF: 0.181 AC: 5593 AN: 30982

GnomAD4 genome AF: 0.186 AC: 28005 AN: 150840 Hom.: 2663 Cov.: 32 AF XY: 0.187 AC XY: 13809 AN XY: 73694

African (AFR) AF: 0.197 AC: 8141 AN: 41346

American (AMR) AF: 0.206 AC: 3128 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 471 AN: 3452

East Asian (EAS) AF: 0.304 AC: 1520 AN: 5002

South Asian (SAS) AF: 0.191 AC: 900 AN: 4712

European-Finnish (FIN) AF: 0.177 AC: 1828 AN: 10350

Middle Eastern (MID) AF: 0.0903 AC: 26 AN: 288

European-Non Finnish (NFE) AF: 0.170 AC: 11485 AN: 67512

Other (OTH) AF: 0.170 AC: 357 AN: 2100

Alfa AF: 0.0757 Hom.: 89

Bravo AF: 0.190

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.92
PhyloP100		0.032
PromoterAI		0.0048	Neutral
Mutation Taster		=299/1	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: rs7649466; hg19: chr3-105587845;