19-18065276-A-G

Variant names:

• chr19-18065276-A-G
• rs438421
• NM_005535.3:c.1483+1266T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005535.3(IL12RB1):​c.1483+1266T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 151,920 control chromosomes in the GnomAD database, including 38,864 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.71 (38864 hom., cov: 30)
• Consequence: IL12RB1 NM_005535.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.82
• Publications: 17 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.1483+1266T>C		intron_variant	Intron 12 of 16	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.1483+1266T>C		intron_variant	Intron 12 of 16	1	NM_005535.3	ENSP00000472165.2
IL12RB1	ENST00000600835.6	c.1483+1266T>C		intron_variant	Intron 13 of 17	1		ENSP00000470788.1

Frequencies

GnomAD3 genomes AF: 0.712 AC: 108043 AN: 151802 Hom.: 38818 Cov.: 30

Gnomad AFR AF: 0.744

Gnomad AMI AF: 0.631

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.733

Gnomad EAS AF: 0.740

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.694

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.712 AC: 108135 AN: 151920 Hom.: 38864 Cov.: 30 AF XY: 0.711 AC XY: 52779 AN XY: 74218

African (AFR) AF: 0.745 AC: 30885 AN: 41466

American (AMR) AF: 0.566 AC: 8617 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.733 AC: 2545 AN: 3472

East Asian (EAS) AF: 0.740 AC: 3806 AN: 5146

South Asian (SAS) AF: 0.763 AC: 3667 AN: 4804

European-Finnish (FIN) AF: 0.734 AC: 7754 AN: 10560

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.715 AC: 48589 AN: 67934

Other (OTH) AF: 0.697 AC: 1470 AN: 2110

Alfa AF: 0.711 Hom.: 111085

Bravo AF: 0.697

Asia WGS AF: 0.761 AC: 2648 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.72
DANN	Benign	0.50
PhyloP100		-1.8
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: rs438421; hg19: chr19-18176086;