rs121434494

Positions:

• chr19-18075812-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The ENST00000593993.7(IL12RB1):​c.637C>T​(p.Arg213Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,459,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R213Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: IL12RB1 ENST00000593993.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.200

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a strand (size 8) in uniprot entity I12R1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000593993.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745
• PP5: Variant 19-18075812-G-A is Pathogenic according to our data. Variant chr19-18075812-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8035.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-18075812-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.637C>T	p.Arg213Trp	missense_variant	7/17	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.637C>T	p.Arg213Trp	missense_variant	7/17	1	NM_005535.3	ENSP00000472165	P1
IL12RB1	ENST00000600835.6	c.637C>T	p.Arg213Trp	missense_variant	8/18	1		ENSP00000470788	P1
IL12RB1	ENST00000322153.11	c.637C>T	p.Arg213Trp	missense_variant	7/10	1		ENSP00000314425

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251294 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1459300 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000631

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 30, 2023	This missense change has been observed in individual(s) with clinical features of mendelian susceptibility to mycobacterial disease (PMID: 11313259, 11424023, 12591909, 21057261, 31367980). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121434494, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 213 of the IL12RB1 protein (p.Arg213Trp). ClinVar contains an entry for this variant (Variation ID: 8035). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects IL12RB1 function (PMID: 11313259, 11424023, 16293671). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IL12RB1 protein function. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 2001	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.71	.;T;T
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.6	.;.;D
REVEL	Benign	0.28
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;B
Vest4		0.68
MutPred		0.81		Loss of disorder (P = 0.0714);Loss of disorder (P = 0.0714);Loss of disorder (P = 0.0714);
MVP		0.60
MPC		0.47
ClinPred		0.74	D
GERP RS		-0.76
Varity_R		0.10
gMVP		0.67

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

Other links and lift over

dbSNP: rs121434494; hg19: chr19-18186622; COSMIC: COSV59098771;