rs17852635

chr19-18075765-G-Achr19-18075765-G-Cchr19-18075765-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005535.3(IL12RB1):c.684C>T(p.Pro228=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,610,226 control chromosomes in the GnomAD database, including 75,834 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P228P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.25 (5580 hom., cov: 31)
  • Exomes 𝑓: 0.31 (70254 hom.)
• Consequence: IL12RB1 NM_005535.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.47

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-18075765-G-A is Benign according to our data. Variant chr19-18075765-G-A is described in ClinVar as [Benign]. Clinvar id is 328596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18075765-G-A is described in Lovd as [Benign]. Variant chr19-18075765-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.47 with no splicing effect.
• 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.684C>T	p.Pro228=	synonymous_variant	7/17	ENST00000593993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB1	ENST00000593993.7	c.684C>T	p.Pro228=	synonymous_variant	7/17	1	NM_005535.3	P1
IL12RB1	ENST00000600835.6	c.684C>T	p.Pro228=	synonymous_variant	8/18	1		P1
IL12RB1	ENST00000322153.11	c.684C>T	p.Pro228=	synonymous_variant	7/10	1

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38678 AN: 151868 Hom.: 5570 Cov.: 31

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.249

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: 0.262

GnomAD3 exomes AF: 0.277 AC: 69678 AN: 251328 Hom.: 10367 AF XY: 0.283 AC XY: 38438 AN XY: 135896

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.336

Gnomad EAS exome AF: 0.354

Gnomad SAS exome AF: 0.226

Gnomad FIN exome AF: 0.326

Gnomad NFE exome AF: 0.321

Gnomad OTH exome AF: 0.280

GnomAD4 exome AF: 0.306 AC: 445884 AN: 1458240 Hom.: 70254 Cov.: 32 AF XY: 0.305 AC XY: 221407 AN XY: 725652

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.333

Gnomad4 EAS exome AF: 0.385

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.325

Gnomad4 NFE exome AF: 0.319

Gnomad4 OTH exome AF: 0.299

GnomAD4 genome AF: 0.255 AC: 38713 AN: 151986 Hom.: 5580 Cov.: 31 AF XY: 0.256 AC XY: 19047 AN XY: 74276

Gnomad4 AFR AF: 0.126

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: 0.297 Hom.: 8973

Bravo AF: 0.239

Asia WGS AF: 0.322 AC: 1120 AN: 3478

EpiCase AF: 0.321

EpiControl AF: 0.316

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not specified Benign:2

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 -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.12
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17852635; hg19: chr19-18186575; COSMIC: COSV59097361;