rs436857

Variant names:

• chr19-18086825-G-A
• rs436857
• NM_005535.3:c.-2C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005535.3(IL12RB1):​c.-2C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,608,412 control chromosomes in the GnomAD database, including 29,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2282 hom., cov: 31)
  • Exomes 𝑓: 0.19 (27493 hom.)
• Consequence: IL12RB1 NM_005535.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.55
• Publications: 51 publications found

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]

IL12RB1 Gene-Disease associations (from GenCC):

• Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-18086825-G-A is Benign according to our data. Variant chr19-18086825-G-A is described in ClinVar as Benign. ClinVar VariationId is 328605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.-2C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 17	ENST00000593993.7	NP_005526.1
IL12RB1	NM_005535.3	c.-2C>T		5_prime_UTR_variant	Exon 1 of 17	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.-2C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 17	1	NM_005535.3	ENSP00000472165.2
IL12RB1	ENST00000593993.7	c.-2C>T		5_prime_UTR_variant	Exon 1 of 17	1	NM_005535.3	ENSP00000472165.2

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25863 AN: 151904 Hom.: 2279 Cov.: 31

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.164 AC: 39257 AN: 239968 AF XY: 0.165

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.0808

Gnomad FIN exome AF: 0.211

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.191 AC: 278309 AN: 1456390 Hom.: 27493 Cov.: 34 AF XY: 0.190 AC XY: 137292 AN XY: 724178

African (AFR) AF: 0.144 AC: 4813 AN: 33352

American (AMR) AF: 0.122 AC: 5409 AN: 44316

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 4940 AN: 26038

East Asian (EAS) AF: 0.151 AC: 5958 AN: 39566

South Asian (SAS) AF: 0.127 AC: 10891 AN: 85636

European-Finnish (FIN) AF: 0.205 AC: 10663 AN: 51964

Middle Eastern (MID) AF: 0.165 AC: 954 AN: 5768

European-Non Finnish (NFE) AF: 0.202 AC: 223840 AN: 1109584

Other (OTH) AF: 0.180 AC: 10841 AN: 60166

GnomAD4 genome AF: 0.170 AC: 25883 AN: 152022 Hom.: 2282 Cov.: 31 AF XY: 0.170 AC XY: 12639 AN XY: 74294

African (AFR) AF: 0.142 AC: 5901 AN: 41484

American (AMR) AF: 0.130 AC: 1990 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 649 AN: 3472

East Asian (EAS) AF: 0.102 AC: 527 AN: 5178

South Asian (SAS) AF: 0.132 AC: 636 AN: 4814

European-Finnish (FIN) AF: 0.217 AC: 2287 AN: 10556

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13387 AN: 67948

Other (OTH) AF: 0.164 AC: 345 AN: 2104

Alfa AF: 0.186 Hom.: 8927

Bravo AF: 0.161

Asia WGS AF: 0.119 AC: 417 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 26% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.86
DANN	Benign	0.82
PhyloP100		-1.6
PromoterAI		-0.058	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs436857; hg19: chr19-18197635; COSMIC: COSV59096447;