rs61734350

chr19-18069637-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005535.3(IL12RB1):c.1098G>A(p.Thr366=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,613,436 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (13 hom.)
• Consequence: IL12RB1 NM_005535.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.46

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=-0.84).
• BP6: Variant 19-18069637-C-T is Benign according to our data. Variant chr19-18069637-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 541824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18069637-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.46 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00242 (369/152322) while in subpopulation NFE AF= 0.00375 (255/68028). AF 95% confidence interval is 0.00337. There are 0 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB1	NM_005535.3	c.1098G>A	p.Thr366=	synonymous_variant	10/17	ENST00000593993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB1	ENST00000593993.7	c.1098G>A	p.Thr366=	synonymous_variant	10/17	1	NM_005535.3	P1
IL12RB1	ENST00000600835.6	c.1098G>A	p.Thr366=	synonymous_variant	11/18	1		P1

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 370 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00290 AC: 721 AN: 248900 Hom.: 2 AF XY: 0.00307 AC XY: 415 AN XY: 135078

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00566

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00317

Gnomad FIN exome AF: 0.000377

Gnomad NFE exome AF: 0.00380

Gnomad OTH exome AF: 0.00397

GnomAD4 exome AF: 0.00298 AC: 4354 AN: 1461114 Hom.: 13 Cov.: 34 AF XY: 0.00311 AC XY: 2262 AN XY: 726868

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.00559

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00308

Gnomad4 FIN exome AF: 0.000490

Gnomad4 NFE exome AF: 0.00313

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.00242 AC: 369 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00200 AC XY: 149 AN XY: 74484

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00310

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00335 Hom.: 0

Bravo AF: 0.00255

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00523

EpiControl AF: 0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	IL12RB1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.086
Dann	Benign	0.57

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: rs61734350; hg19: chr19-18180447;