19-18082803-A-G

Variant names:

• chr19-18082803-A-G
• rs439409
• NM_005535.3:c.125-539T>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.125-539T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 152,050 control chromosomes in the GnomAD database, including 40,447 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 0.73 (40447 hom., cov: 32)
• Consequence: IL12RB1 NM_005535.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54
• Publications: 4 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005535.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	NM_005535.3	MANE Select	c.125-539T>C		intron	N/A	NP_005526.1	P42701-1
	IL12RB1	NM_001290024.2		c.245-539T>C		intron	N/A	NP_001276953.1
	IL12RB1	NM_001440424.1		c.125-539T>C		intron	N/A	NP_001427353.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.125-539T>C		intron	N/A	ENSP00000472165.2	P42701-1
	IL12RB1	ENST00000600835.6	TSL:1	c.125-539T>C		intron	N/A	ENSP00000470788.1	P42701-1
	IL12RB1	ENST00000322153.11	TSL:1	c.125-539T>C		intron	N/A	ENSP00000314425.5	P42701-3

Frequencies

GnomAD3 genomes AF: 0.726 AC: 110235 AN: 151932 Hom.: 40422 Cov.: 32

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.754

Gnomad AMR AF: 0.680

Gnomad ASJ AF: 0.795

Gnomad EAS AF: 0.938

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.793

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.719

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

GnomAD4 genome AF: 0.726 AC: 110314 AN: 152050 Hom.: 40447 Cov.: 32 AF XY: 0.730 AC XY: 54248 AN XY: 74328

African (AFR) AF: 0.637 AC: 26387 AN: 41424

American (AMR) AF: 0.679 AC: 10370 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 2757 AN: 3468

East Asian (EAS) AF: 0.938 AC: 4861 AN: 5182

South Asian (SAS) AF: 0.832 AC: 4015 AN: 4828

European-Finnish (FIN) AF: 0.793 AC: 8392 AN: 10586

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.752 AC: 51103 AN: 67984

Other (OTH) AF: 0.722 AC: 1523 AN: 2108

Alfa AF: 0.740 Hom.: 15391

Bravo AF: 0.708

Asia WGS AF: 0.870 AC: 3024 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.6
DANN	Benign	0.20
PhyloP100		-1.5
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: rs439409; hg19: chr19-18193613;