rs554063682

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000593993.7(IL12RB1):​c.1791+2T>G variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000743 in 1,548,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

IL12RB1
ENST00000593993.7 splice_donor

Scores

1
3
3
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.33
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 Pathogenic. Variant got 18 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-18061120-A-C is Pathogenic according to our data. Variant chr19-18061120-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 579038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18061120-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
IL12RB1NM_005535.3 linkuse as main transcriptc.1791+2T>G splice_donor_variant ENST00000593993.7 NP_005526.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
IL12RB1ENST00000593993.7 linkuse as main transcriptc.1791+2T>G splice_donor_variant 1 NM_005535.3 ENSP00000472165 P1P42701-1
IL12RB1ENST00000600835.6 linkuse as main transcriptc.1791+2T>G splice_donor_variant 1 ENSP00000470788 P1P42701-1

Frequencies

GnomAD3 genomes
AF:
0.0000856
AC:
13
AN:
151870
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000968
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000624
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000111
AC:
26
AN:
233196
Hom.:
0
AF XY:
0.000127
AC XY:
16
AN XY:
125906
show subpopulations
Gnomad AFR exome
AF:
0.0000708
Gnomad AMR exome
AF:
0.000123
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000107
Gnomad FIN exome
AF:
0.0000975
Gnomad NFE exome
AF:
0.000152
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000730
AC:
102
AN:
1396386
Hom.:
0
Cov.:
26
AF XY:
0.0000689
AC XY:
48
AN XY:
696568
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000117
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000768
Gnomad4 SAS exome
AF:
0.0000723
Gnomad4 FIN exome
AF:
0.0000379
Gnomad4 NFE exome
AF:
0.0000804
Gnomad4 OTH exome
AF:
0.0000172
GnomAD4 genome
AF:
0.0000855
AC:
13
AN:
151984
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000624
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000736
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000130
Hom.:
0
Bravo
AF:
0.0000831
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ExAC
AF:
0.000157
AC:
19

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency Pathogenic:3
Pathogenic, no assertion criteria providedclinical testingBiochemical Molecular Genetic Laboratory, King Abdulaziz Medical CitySep 10, 2020- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 20, 2023For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 579038). Disruption of this splice site has been observed in individual(s) with IL12RB1 deficiency (PMID: 12591909, 21057261, 27141500). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs554063682, gnomAD 0.01%). This sequence change affects a donor splice site in intron 15 of the IL12RB1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IL12RB1 are known to be pathogenic (PMID: 9603733, 12591909). -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The splice donor variant c.1791+2T>G in IL12RB1 (NM_005535.3) has been reported previously in affected individuals with mendelian susceptibility to tuberculosis (Sarrafzadeh SA et al; de Beaucoudrey L et al; Fieschi C et al). This variant has been submitted to Clinvar as Pathogenic. It affects an invariant splice site and hence is predicted to cause loss of function. For these reasons, this variant has been classified as Pathogenic -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsJun 26, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Benign
-0.31
CADD
Uncertain
25
DANN
Benign
0.91
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Uncertain
0.90
D
MutationTaster
Benign
1.0
D
GERP RS
2.5

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.77
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.99
Position offset: 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: rs554063682; hg19: chr19-18171930; API