rs121434492

chr19-18083462-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005535.3(IL12RB1):c.94C>T(p.Gln32Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,613,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: IL12RB1 NM_005535.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.38

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 78 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-18083462-G-A is Pathogenic according to our data. Variant chr19-18083462-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18083462-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB1	NM_005535.3	c.94C>T	p.Gln32Ter	stop_gained	2/17	ENST00000593993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB1	ENST00000593993.7	c.94C>T	p.Gln32Ter	stop_gained	2/17	1	NM_005535.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000835 AC: 21 AN: 251376 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135884

Gnomad AFR exome AF: 0.0000615

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: 0.000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000172 AC: 251 AN: 1461638 Hom.: 0 Cov.: 31 AF XY: 0.000160 AC XY: 116 AN XY: 727102

Gnomad4 AFR exome AF: 0.0000299

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: 0.000223

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000987 AC: 15 AN: 152002 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74236

Gnomad4 AFR AF: 0.000145

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: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000189 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2018	- -

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 29, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 29, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 25, 2023	This sequence change creates a premature translational stop signal (p.Gln32*) in the IL12RB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IL12RB1 are known to be pathogenic (PMID: 9603733, 12591909). This variant is present in population databases (rs121434492, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Mendelian susceptibility to mycobacterial disease (PMID: 9603733). ClinVar contains an entry for this variant (Variation ID: 8032). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.73	D
MutationTaster	Benign	1.0	A;A
Vest4		0.70
GERP RS		1.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: 29

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434492; hg19: chr19-18194272;