rs141968777

chr19-18063910-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.1584G>A(p.Arg528=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00418 in 1,613,508 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 30)
  • Exomes 𝑓: 0.0043 (30 hom.)
• Consequence: IL12RB1 NM_005535.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.85

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=-0.72).
• BP6: Variant 19-18063910-C-T is Benign according to our data. Variant chr19-18063910-C-T is described in ClinVar as [Benign]. Clinvar id is 328579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18063910-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00338 (515/152228) while in subpopulation SAS AF= 0.0127 (61/4822). AF 95% confidence interval is 0.0101. There are 2 homozygotes in gnomad4. There are 279 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB1	NM_005535.3	c.1584G>A	p.Arg528=	synonymous_variant	13/17	ENST00000593993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB1	ENST00000593993.7	c.1584G>A	p.Arg528=	synonymous_variant	13/17	1	NM_005535.3	P1
IL12RB1	ENST00000600835.6	c.1584G>A	p.Arg528=	synonymous_variant	14/18	1		P1

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152108 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00473 AC: 1174 AN: 247948 Hom.: 9 AF XY: 0.00542 AC XY: 730 AN XY: 134572

Gnomad AFR exome AF: 0.000326

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0110

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.00434

Gnomad OTH exome AF: 0.00416

GnomAD4 exome AF: 0.00427 AC: 6235 AN: 1461280 Hom.: 30 Cov.: 31 AF XY: 0.00459 AC XY: 3335 AN XY: 726910

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0129

Gnomad4 FIN exome AF: 0.0127

Gnomad4 NFE exome AF: 0.00370

Gnomad4 OTH exome AF: 0.00368

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152228 Hom.: 2 Cov.: 30 AF XY: 0.00375 AC XY: 279 AN XY: 74408

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0127

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.00371

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00336 Hom.: 0

Bravo AF: 0.00241

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 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. -

IL12RB1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2022

IL12RB1: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.65
Dann	Benign	0.88

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: rs141968777; hg19: chr19-18174720; COSMIC: COSV105942360;