chr3-105702188-C-G

Variant names:

• chr3-105702188-C-G
• rs41302192
• NM_170662.5:c.1865G>C

Variant summary

Our verdict is Benign. The variant received -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. 16/20 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
• Publications: 19 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 -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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
CBLB	NM_170662.5	c.1865G>C	p.Ser622Thr	missense_variant	Exon 12 of 19	ENST00000394030.8	NP_733762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBLB	ENST00000394030.8	c.1865G>C	p.Ser622Thr	missense_variant	Exon 12 of 19	1	NM_170662.5	ENSP00000377598.4

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

GnomAD2 exomes AF: 0.00583 AC: 1464 AN: 251188 AF XY: 0.00603

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 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

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.00165 AC: 74 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00834 AC: 218 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00530 AC: 457 AN: 86256

European-Finnish (FIN) AF: 0.00914 AC: 488 AN: 53420

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5768

European-Non Finnish (NFE) AF: 0.00730 AC: 8121 AN: 1112002

Other (OTH) AF: 0.00631 AC: 381 AN: 60396

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

African (AFR) AF: 0.00108 AC: 45 AN: 41534

American (AMR) AF: 0.00183 AC: 28 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4820

European-Finnish (FIN) AF: 0.00641 AC: 68 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00723 AC: 492 AN: 68018

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 27, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CBLB: BP4, BS2 -

CBLB-related disorder Benign:1

Feb 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

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
PhyloP100		0.59
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
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs41302192; hg19: chr3-105421032;