rs2045386

Variant names:

• chr19-18071456-G-A
• rs2045386
• NM_005535.3:c.1021+656C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005535.3(IL12RB1):​c.1021+656C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 462,620 control chromosomes in the GnomAD database, including 40,306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.38 (11269 hom., cov: 32)
  • Exomes 𝑓: 0.43 (29037 hom.)
• Consequence: IL12RB1 NM_005535.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.280
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 19-18071456-G-A is Benign according to our data. Variant chr19-18071456-G-A is described in ClinVar as Benign. ClinVar VariationId is 2688426.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.1021+656C>T		intron_variant	Intron 9 of 16	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.1021+656C>T		intron_variant	Intron 9 of 16	1	NM_005535.3	ENSP00000472165.2
IL12RB1	ENST00000600835.6	c.1021+656C>T		intron_variant	Intron 10 of 17	1		ENSP00000470788.1
IL12RB1	ENST00000322153.11	c.1022-123C>T		intron_variant	Intron 9 of 9	1		ENSP00000314425.5

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57812 AN: 151792 Hom.: 11270 Cov.: 32

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.381

GnomAD4 exome AF: 0.430 AC: 133603 AN: 310710 Hom.: 29037 AF XY: 0.439 AC XY: 74483 AN XY: 169700

African (AFR) AF: 0.313 AC: 2096 AN: 6688

American (AMR) AF: 0.346 AC: 4442 AN: 12824

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 3060 AN: 6912

East Asian (EAS) AF: 0.373 AC: 2872 AN: 7690

South Asian (SAS) AF: 0.522 AC: 24881 AN: 47664

European-Finnish (FIN) AF: 0.405 AC: 4056 AN: 10006

Middle Eastern (MID) AF: 0.417 AC: 684 AN: 1642

European-Non Finnish (NFE) AF: 0.421 AC: 85816 AN: 203802

Other (OTH) AF: 0.422 AC: 5696 AN: 13482

GnomAD4 genome AF: 0.381 AC: 57836 AN: 151910 Hom.: 11269 Cov.: 32 AF XY: 0.382 AC XY: 28330 AN XY: 74244

African (AFR) AF: 0.313 AC: 12962 AN: 41434

American (AMR) AF: 0.337 AC: 5133 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1567 AN: 3470

East Asian (EAS) AF: 0.360 AC: 1854 AN: 5146

South Asian (SAS) AF: 0.526 AC: 2535 AN: 4822

European-Finnish (FIN) AF: 0.415 AC: 4385 AN: 10554

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.414 AC: 28096 AN: 67936

Other (OTH) AF: 0.380 AC: 801 AN: 2106

Alfa AF: 0.382 Hom.: 7633

Bravo AF: 0.369

Asia WGS AF: 0.419 AC: 1457 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

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 44% of patients studied by a panel of primary immunodeficiencies. Number of patients: 39. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.0
DANN	Benign	0.21
PhyloP100		0.28
Mutation Taster		=100/0	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: rs2045386; hg19: chr19-18182266;