rs429774

Variant names:

• chr19-18075942-T-C
• rs429774
• NM_005535.3:c.581-74A>G

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.581-74A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,448,160 control chromosomes in the GnomAD database, including 68,585 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6126 hom., cov: 31)
  • Exomes 𝑓: 0.31 (62459 hom.)
• Consequence: IL12RB1 NM_005535.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.877
• Publications: 27 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=-0.93).
• BP6: Variant 19-18075942-T-C is Benign according to our data. Variant chr19-18075942-T-C is described in ClinVar as Benign. ClinVar VariationId is 2688447.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.581-74A>G		intron_variant	Intron 6 of 16	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.581-74A>G		intron_variant	Intron 6 of 16	1	NM_005535.3	ENSP00000472165.2
IL12RB1	ENST00000600835.6	c.581-74A>G		intron_variant	Intron 7 of 17	1		ENSP00000470788.1
IL12RB1	ENST00000322153.11	c.581-74A>G		intron_variant	Intron 6 of 9	1		ENSP00000314425.5

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42047 AN: 151938 Hom.: 6111 Cov.: 31

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.278

GnomAD4 exome AF: 0.306 AC: 396624 AN: 1296104 Hom.: 62459 AF XY: 0.305 AC XY: 199155 AN XY: 653078

African (AFR) AF: 0.191 AC: 5770 AN: 30134

American (AMR) AF: 0.171 AC: 7623 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 8323 AN: 25126

East Asian (EAS) AF: 0.385 AC: 14972 AN: 38892

South Asian (SAS) AF: 0.229 AC: 18932 AN: 82758

European-Finnish (FIN) AF: 0.325 AC: 17072 AN: 52520

Middle Eastern (MID) AF: 0.303 AC: 1643 AN: 5428

European-Non Finnish (NFE) AF: 0.318 AC: 305692 AN: 961866

Other (OTH) AF: 0.302 AC: 16597 AN: 54868

GnomAD4 genome AF: 0.277 AC: 42102 AN: 152056 Hom.: 6126 Cov.: 31 AF XY: 0.278 AC XY: 20637 AN XY: 74320

African (AFR) AF: 0.204 AC: 8451 AN: 41510

American (AMR) AF: 0.215 AC: 3278 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1118 AN: 3472

East Asian (EAS) AF: 0.370 AC: 1913 AN: 5170

South Asian (SAS) AF: 0.237 AC: 1144 AN: 4824

European-Finnish (FIN) AF: 0.337 AC: 3551 AN: 10552

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.320 AC: 21755 AN: 67968

Other (OTH) AF: 0.282 AC: 594 AN: 2106

Alfa AF: 0.302 Hom.: 12455

Bravo AF: 0.264

Asia WGS AF: 0.326 AC: 1134 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 36% of patients studied by a panel of primary immunodeficiencies. Number of patients: 32. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.3
DANN	Benign	0.49
PhyloP100		-0.88
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: rs429774; hg19: chr19-18186752; COSMIC: COSV59097392; COSMIC: COSV59097392;