NM_170662.5:c.2613T>C

Variant names:

• chr3-105670309-A-G
• rs11713094
• NM_170662.5:c.2613T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_170662.5(CBLB):​c.2613T>C​(p.Pro871Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,609,800 control chromosomes in the GnomAD database, including 38,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Synonymous variant affecting the same amino acid position (i.e. P871P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.22 (3819 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34672 hom.)
• Consequence: CBLB NM_170662.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.769
• Publications: 17 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 3-105670309-A-G is Benign according to our data. Variant chr3-105670309-A-G is described in ClinVar as Benign. ClinVar VariationId is 3056926.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.769 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.251 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLB	NM_170662.5	MANE Select	c.2613T>C	p.Pro871Pro	synonymous	Exon 18 of 19	NP_733762.2	Q13191-1
	CBLB	NM_001321786.1		c.2697T>C	p.Pro899Pro	synonymous	Exon 18 of 19	NP_001308715.1
	CBLB	NM_001321788.2		c.2613T>C	p.Pro871Pro	synonymous	Exon 18 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.2613T>C	p.Pro871Pro	synonymous	Exon 18 of 19	ENSP00000377598.4	Q13191-1
	CBLB	ENST00000476370.1	TSL:1	n.3685T>C		non_coding_transcript_exon	Exon 1 of 2
	CBLB	ENST00000954009.1		c.2697T>C	p.Pro899Pro	synonymous	Exon 19 of 20	ENSP00000624068.1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33517 AN: 151948 Hom.: 3812 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.193

GnomAD2 exomes AF: 0.223 AC: 55670 AN: 249796 AF XY: 0.216

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.214

Gnomad FIN exome AF: 0.273

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.215 AC: 312961 AN: 1457734 Hom.: 34672 Cov.: 29 AF XY: 0.212 AC XY: 153919 AN XY: 725430

African (AFR) AF: 0.229 AC: 7638 AN: 33352

American (AMR) AF: 0.315 AC: 14058 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3669 AN: 26092

East Asian (EAS) AF: 0.220 AC: 8721 AN: 39606

South Asian (SAS) AF: 0.145 AC: 12457 AN: 86196

European-Finnish (FIN) AF: 0.271 AC: 14437 AN: 53334

Middle Eastern (MID) AF: 0.140 AC: 803 AN: 5754

European-Non Finnish (NFE) AF: 0.215 AC: 238469 AN: 1108480

Other (OTH) AF: 0.211 AC: 12709 AN: 60248

GnomAD4 genome AF: 0.221 AC: 33542 AN: 152066 Hom.: 3819 Cov.: 32 AF XY: 0.224 AC XY: 16630 AN XY: 74332

African (AFR) AF: 0.223 AC: 9233 AN: 41496

American (AMR) AF: 0.258 AC: 3937 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 494 AN: 3472

East Asian (EAS) AF: 0.216 AC: 1117 AN: 5166

South Asian (SAS) AF: 0.147 AC: 709 AN: 4828

European-Finnish (FIN) AF: 0.268 AC: 2834 AN: 10574

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14544 AN: 67958

Other (OTH) AF: 0.193 AC: 408 AN: 2112

Alfa AF: 0.212 Hom.: 1598

Bravo AF: 0.221

Asia WGS AF: 0.158 AC: 548 AN: 3478

EpiCase AF: 0.209

EpiControl AF: 0.200

ClinVar

ClinVar submissions

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	-0.45
CADD	Benign	3.5
DANN	Benign	0.72
PhyloP100		0.77
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: rs11713094; hg19: chr3-105389153; COSMIC: COSV51421203;