rs2045386

Positions:

• chr19-18071456-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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/exons	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.1021+656C>T		intron_variant		ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.1021+656C>T		intron_variant		1	NM_005535.3	ENSP00000472165	P1
IL12RB1	ENST00000322153.11	c.1022-123C>T		intron_variant		1		ENSP00000314425
IL12RB1	ENST00000600835.6	c.1021+656C>T		intron_variant		1		ENSP00000470788	P1

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

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.346

Gnomad4 ASJ exome AF: 0.443

Gnomad4 EAS exome AF: 0.373

Gnomad4 SAS exome AF: 0.522

Gnomad4 FIN exome AF: 0.405

Gnomad4 NFE exome AF: 0.421

Gnomad4 OTH exome AF: 0.422

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

Gnomad4 AFR AF: 0.313

Gnomad4 AMR AF: 0.337

Gnomad4 ASJ AF: 0.452

Gnomad4 EAS AF: 0.360

Gnomad4 SAS AF: 0.526

Gnomad4 FIN AF: 0.415

Gnomad4 NFE AF: 0.414

Gnomad4 OTH AF: 0.380

Alfa AF: 0.398 Hom.: 3182

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

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 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

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: rs2045386; hg19: chr19-18182266;