Genetic Variant NM_001321790.2:c.20C>T (chr3-105869369-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001321790.2(CBLB):c.20C>T(p.Pro7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000168 in 1,190,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P7R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

CBLB
NM_001321790.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.40

Publications

0 publications found

Variant links:

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)

CBLB links:

ENSG00000288848 (HGNC:):

ENSG00000288848 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07922149).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
CBLB	NM_001321790.2 link	c.20C>T	p.Pro7Leu	missense_variant	Exon 1 of 18	NP_001308719.1
CBLB	XM_017007395.2 link	c.20C>T	p.Pro7Leu	missense_variant	Exon 1 of 19	XP_016862884.1
CBLB	XM_017007398.2 link	c.20C>T	p.Pro7Leu	missense_variant	Exon 1 of 18	XP_016862887.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
CBLB	ENST00000438603.6 link	c.20C>T	p.Pro7Leu	missense_variant	Exon 1 of 4	4	ENSP00000409750.2	C9JRB3
CBLB	ENST00000643322.1 link	n.20C>T		non_coding_transcript_exon_variant	Exon 1 of 21		ENSP00000496352.1	A0A2R8YFD4
ENSG00000288848	ENST00000690303.3 link	n.250G>A		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000168

AC:

AN:

1190620

Hom.:

Cov.:

AF XY:

0.00000172

AC XY:

AN XY:

582822

show subpopulations

African (AFR)

AF:

0.0000773

AC:

AN:

25882

American (AMR)

AF:

0.00

AC:

AN:

29242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18372

East Asian (EAS)

AF:

0.00

AC:

AN:

20006

South Asian (SAS)

AF:

0.00

AC:

AN:

76546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4656

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

943734

Other (OTH)

AF:

0.00

AC:

AN:

44808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.21

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.32

M_CAP

Benign

0.018

MetaRNN

Benign

0.079

MetaSVM

Benign

-0.92

PhyloP100

1.4

PROVEAN

Benign

-0.060

REVEL

Benign

0.15

Sift

Benign

0.48

MutPred

0.12

Loss of disorder (P = 0.0483);

MVP

0.17

ClinPred

0.15

GERP RS

2.4

PromoterAI

0.0012

Neutral

(source)

Mutation Taster

=99/1

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over