rs11575926

Positions:

• chr19-18077598-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_005535.3(IL12RB1):​c.467G>A​(p.Arg156His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,597,014 control chromosomes in the GnomAD database, including 22,380 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1420 hom., cov: 31)
  • Exomes 𝑓: 0.16 (20960 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.41

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 Benign. Variant got -18 ACMG points.

• PM1: In a domain Fibronectin type-III 2 (size 92) in uniprot entity I12R1_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_005535.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.002072394).
• BP6: Variant 19-18077598-C-T is Benign according to our data. Variant chr19-18077598-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 328598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18077598-C-T is described in Lovd as [Benign]. Variant chr19-18077598-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.467G>A	p.Arg156His	missense_variant	5/17	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.467G>A	p.Arg156His	missense_variant	5/17	1	NM_005535.3	ENSP00000472165.2
IL12RB1	ENST00000600835.6	c.467G>A	p.Arg156His	missense_variant	6/18	1		ENSP00000470788.1
IL12RB1	ENST00000322153.11	c.467G>A	p.Arg156His	missense_variant	5/10	1		ENSP00000314425.5

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18197 AN: 152004 Hom.: 1419 Cov.: 31

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.0919

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0796

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.123

GnomAD3 exomes AF: 0.127 AC: 31791 AN: 250760 Hom.: 2536 AF XY: 0.130 AC XY: 17621 AN XY: 135578

Gnomad AFR exome AF: 0.0283

Gnomad AMR exome AF: 0.0677

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.0792

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.163 AC: 234981 AN: 1444892 Hom.: 20960 Cov.: 27 AF XY: 0.161 AC XY: 115887 AN XY: 719732

Gnomad4 AFR exome AF: 0.0236

Gnomad4 AMR exome AF: 0.0695

Gnomad4 ASJ exome AF: 0.191

Gnomad4 EAS exome AF: 0.000530

Gnomad4 SAS exome AF: 0.0819

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.120 AC: 18201 AN: 152122 Hom.: 1420 Cov.: 31 AF XY: 0.119 AC XY: 8830 AN XY: 74338

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.0918

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0810

Gnomad4 FIN AF: 0.198

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.122

Alfa AF: 0.152 Hom.: 895

Bravo AF: 0.108

TwinsUK AF: 0.179 AC: 665

ALSPAC AF: 0.189 AC: 729

ESP6500AA AF: 0.0359 AC: 158

ESP6500EA AF: 0.174 AC: 1494

ExAC AF: 0.126 AC: 15244

Asia WGS AF: 0.0350 AC: 123 AN: 3478

EpiCase AF: 0.174

EpiControl AF: 0.167

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Immunodeficiency 27A Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 09, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.16
DANN	Benign	0.88
DEOGEN2	Benign	0.21	T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.71	.;T;T
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L;L
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.1	.;.;N
REVEL	Benign	0.13
Sift4G	Benign	0.093	T;T;T
Polyphen		0.014	B;B;B
Vest4		0.039
MPC		0.11
ClinPred		0.0016	T
GERP RS		-7.8
Varity_R		0.021
gMVP		0.28

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: rs11575926; hg19: chr19-18188408; COSMIC: COSV59097132; COSMIC: COSV59097132;