rs11575934

chr19-18075808-T-C

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.641A>G(p.Gln214Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,611,352 control chromosomes in the GnomAD database, including 75,833 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 0.25 (5580 hom., cov: 32)
  • Exomes 𝑓: 0.31 (70253 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.194

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005535.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0024283528).
• BP6: Variant 19-18075808-T-C is Benign according to our data. Variant chr19-18075808-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 328597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18075808-T-C is described in Lovd as [Benign]. Variant chr19-18075808-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB1	NM_005535.3	c.641A>G	p.Gln214Arg	missense_variant	7/17	ENST00000593993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB1	ENST00000593993.7	c.641A>G	p.Gln214Arg	missense_variant	7/17	1	NM_005535.3	P1
IL12RB1	ENST00000600835.6	c.641A>G	p.Gln214Arg	missense_variant	8/18	1		P1
IL12RB1	ENST00000322153.11	c.641A>G	p.Gln214Arg	missense_variant	7/10	1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38637 AN: 151984 Hom.: 5570 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.261

GnomAD3 exomes AF: 0.277 AC: 69637 AN: 251238 Hom.: 10362 AF XY: 0.283 AC XY: 38412 AN XY: 135874

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.336

Gnomad EAS exome AF: 0.354

Gnomad SAS exome AF: 0.225

Gnomad FIN exome AF: 0.326

Gnomad NFE exome AF: 0.321

Gnomad OTH exome AF: 0.280

GnomAD4 exome AF: 0.306 AC: 446325 AN: 1459250 Hom.: 70253 Cov.: 32 AF XY: 0.305 AC XY: 221603 AN XY: 726102

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.333

Gnomad4 EAS exome AF: 0.385

Gnomad4 SAS exome AF: 0.230

Gnomad4 FIN exome AF: 0.325

Gnomad4 NFE exome AF: 0.319

Gnomad4 OTH exome AF: 0.299

GnomAD4 genome AF: 0.254 AC: 38675 AN: 152102 Hom.: 5580 Cov.: 32 AF XY: 0.256 AC XY: 19037 AN XY: 74340

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.371

Gnomad4 SAS AF: 0.239

Gnomad4 FIN AF: 0.337

Gnomad4 NFE AF: 0.320

Gnomad4 OTH AF: 0.266

Alfa AF: 0.312 Hom.: 13145

Bravo AF: 0.238

TwinsUK AF: 0.312 AC: 1158

ALSPAC AF: 0.323 AC: 1244

ESP6500AA AF: 0.131 AC: 578

ESP6500EA AF: 0.316 AC: 2715

ExAC AF: 0.276 AC: 33563

Asia WGS AF: 0.322 AC: 1121 AN: 3478

EpiCase AF: 0.321

EpiControl AF: 0.316

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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, no convincing disease association -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 31. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.021
Dann	Benign	0.11
DEOGEN2	Benign	0.080	T;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0010	N
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N;N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.24	T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.038
MPC		0.090
ClinPred		0.0042	T
GERP RS		1.7
Varity_R		0.018
gMVP		0.31

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: rs11575934; hg19: chr19-18186618; COSMIC: COSV59097375;