rs41302192

Positions:

• chr3-105702188-C-G
• chr3-105702188-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_170662.5(CBLB):​c.1865G>C​(p.Ser622Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00653 in 1,614,136 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (4 hom., cov: 30)
  • Exomes 𝑓: 0.0067 (64 hom.)
• Consequence: CBLB NM_170662.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.588

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064592063).
• BP6: Variant 3-105702188-C-G is Benign according to our data. Variant chr3-105702188-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 133823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBLB	NM_170662.5	c.1865G>C	p.Ser622Thr	missense_variant	12/19	ENST00000394030.8	NP_733762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBLB	ENST00000394030.8	c.1865G>C	p.Ser622Thr	missense_variant	12/19	1	NM_170662.5	ENSP00000377598	P1

Frequencies

GnomAD3 genomes AF: 0.00459 AC: 698 AN: 152138 Hom.: 4 Cov.: 30

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00641

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00723

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00583 AC: 1464 AN: 251188 Hom.: 8 AF XY: 0.00603 AC XY: 818 AN XY: 135734

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00454

Gnomad FIN exome AF: 0.00855

Gnomad NFE exome AF: 0.00823

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.00673 AC: 9838 AN: 1461880 Hom.: 64 Cov.: 34 AF XY: 0.00683 AC XY: 4968 AN XY: 727238

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00834

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00530

Gnomad4 FIN exome AF: 0.00914

Gnomad4 NFE exome AF: 0.00730

Gnomad4 OTH exome AF: 0.00631

GnomAD4 genome AF: 0.00458 AC: 697 AN: 152256 Hom.: 4 Cov.: 30 AF XY: 0.00458 AC XY: 341 AN XY: 74456

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00641

Gnomad4 NFE AF: 0.00723

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00619 Hom.: 7

Bravo AF: 0.00443

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00733 AC: 63

ExAC AF: 0.00600 AC: 728

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00807

EpiControl AF: 0.00901

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 27, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	CBLB: BP4, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CBLB-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Benign	0.71
DEOGEN2	Benign	0.25	T;T;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.72	.;T;T;T
MetaRNN	Benign	0.0065	T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.4	L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.29	.;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.41	.;T;.;T
Sift4G	Benign	0.34	.;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.084, 0.12, 0.080
MVP		0.45
MPC		0.047
ClinPred		0.0012	T
GERP RS		3.8
Varity_R		0.033

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs41302192; hg19: chr3-105421032;