19-18069654-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005535.3(IL12RB1):ā€‹c.1081C>Gā€‹(p.Arg361Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.000012 ( 0 hom. )

Consequence

IL12RB1
NM_005535.3 missense

Scores

1
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0890
Variant links:
Genes affected
IL12RB1 (HGNC:5971): (interleukin 12 receptor subunit beta 1) The protein encoded by this gene is a type I transmembrane protein that belongs to the hemopoietin receptor superfamily. This protein binds to interleukine 12 (IL12) with a low affinity, and is thought to be a part of IL12 receptor complex. This protein forms a disulfide-linked oligomer, which is required for its IL12 binding activity. The coexpression of this and IL12RB2 proteins was shown to lead to the formation of high-affinity IL12 binding sites and reconstitution of IL12 dependent signaling. Mutations in this gene impair the development of interleukin-17-producing T lymphocytes and result in increased susceptibility to mycobacterial and Salmonella infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.17333671).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IL12RB1NM_005535.3 linkc.1081C>G p.Arg361Gly missense_variant Exon 10 of 17 ENST00000593993.7 NP_005526.1 P42701-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IL12RB1ENST00000593993.7 linkc.1081C>G p.Arg361Gly missense_variant Exon 10 of 17 1 NM_005535.3 ENSP00000472165.2 P42701-1
IL12RB1ENST00000600835.6 linkc.1081C>G p.Arg361Gly missense_variant Exon 11 of 18 1 ENSP00000470788.1 P42701-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000803
AC:
2
AN:
248962
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135102
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1460784
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
726752
show subpopulations
Gnomad4 AFR exome
AF:
0.000418
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152298
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
ExAC
AF:
0.00000826
AC:
1
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency Uncertain:1
Oct 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 361 of the IL12RB1 protein (p.Arg361Gly). This variant is present in population databases (rs150261140, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with IL12RB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 965371). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt IL12RB1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
4.2
DANN
Benign
0.97
DEOGEN2
Benign
0.23
T;T
Eigen
Benign
-0.60
Eigen_PC
Benign
-0.75
FATHMM_MKL
Benign
0.027
N
LIST_S2
Benign
0.50
.;T
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-0.70
T
MutationAssessor
Benign
1.3
L;L
PrimateAI
Benign
0.20
T
Sift4G
Benign
0.063
T;T
Polyphen
0.83
P;P
Vest4
0.099
MutPred
0.38
Gain of catalytic residue at A360 (P = 0.0798);Gain of catalytic residue at A360 (P = 0.0798);
MVP
0.84
MPC
0.11
ClinPred
0.49
T
GERP RS
0.22
Varity_R
0.13
gMVP
0.41

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs150261140; hg19: chr19-18180464; API