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
Consequence
ENST00000593993.7 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
IL12RB1 | NM_005535.3 | c.1791+2T>G | splice_donor_variant | ENST00000593993.7 | NP_005526.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IL12RB1 | ENST00000593993.7 | c.1791+2T>G | splice_donor_variant | 1 | NM_005535.3 | ENSP00000472165 | P1 | |||
IL12RB1 | ENST00000600835.6 | c.1791+2T>G | splice_donor_variant | 1 | ENSP00000470788 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000856 AC: 13AN: 151870Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000111 AC: 26AN: 233196Hom.: 0 AF XY: 0.000127 AC XY: 16AN XY: 125906
GnomAD4 exome AF: 0.0000730 AC: 102AN: 1396386Hom.: 0 Cov.: 26 AF XY: 0.0000689 AC XY: 48AN XY: 696568
GnomAD4 genome AF: 0.0000855 AC: 13AN: 151984Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74284
ClinVar
Submissions by phenotype
Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 10, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 20, 2023 | For 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 submitter | clinical testing | Neuberg 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 submitter | clinical testing | Blueprint Genetics | Jun 26, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at