rs11574790

Variant names:

• chr5-159316838-G-A
• rs11574790
• NM_002187.3:c.856-22C>T

Variant summary

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

The NM_002187.3(IL12B):​c.856-22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,612,714 control chromosomes in the GnomAD database, including 11,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1471 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9707 hom.)
• Consequence: IL12B NM_002187.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.292
• Publications: 27 publications found

Genes affected

IL12B (HGNC:5970): (interleukin 12B) This gene encodes a subunit of interleukin 12, a cytokine that acts on T and natural killer cells, and has a broad array of biological activities. Interleukin 12 is a disulfide-linked heterodimer composed of the 40 kD cytokine receptor like subunit encoded by this gene, and a 35 kD subunit encoded by IL12A. This cytokine is expressed by activated macrophages that serve as an essential inducer of Th1 cells development. This cytokine has been found to be important for sustaining a sufficient number of memory/effector Th1 cells to mediate long-term protection to an intracellular pathogen. Overexpression of this gene was observed in the central nervous system of patients with multiple sclerosis (MS), suggesting a role of this cytokine in the pathogenesis of the disease. The promoter polymorphism of this gene has been reported to be associated with the severity of atopic and non-atopic asthma in children. [provided by RefSeq, Jul 2008]

IL12B Gene-Disease associations (from GenCC):

• Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000249738 (HGNC:58156):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 5-159316838-G-A is Benign according to our data. Variant chr5-159316838-G-A is described in ClinVar as [Benign]. Clinvar id is 2628273.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12B	NM_002187.3	c.856-22C>T		intron_variant	Intron 6 of 7	ENST00000231228.3	NP_002178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12B	ENST00000231228.3	c.856-22C>T		intron_variant	Intron 6 of 7	1	NM_002187.3	ENSP00000231228.2

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20124 AN: 152132 Hom.: 1464 Cov.: 33

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.0402

Gnomad SAS AF: 0.0647

Gnomad FIN AF: 0.0709

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.116 AC: 28627 AN: 245750 AF XY: 0.111

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.0458

Gnomad FIN exome AF: 0.0729

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.110 AC: 161074 AN: 1460464 Hom.: 9707 Cov.: 32 AF XY: 0.109 AC XY: 78930 AN XY: 726546

African (AFR) AF: 0.197 AC: 6589 AN: 33448

American (AMR) AF: 0.187 AC: 8361 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 4611 AN: 26122

East Asian (EAS) AF: 0.0417 AC: 1656 AN: 39698

South Asian (SAS) AF: 0.0715 AC: 6164 AN: 86244

European-Finnish (FIN) AF: 0.0721 AC: 3827 AN: 53072

Middle Eastern (MID) AF: 0.189 AC: 1087 AN: 5762

European-Non Finnish (NFE) AF: 0.110 AC: 121704 AN: 1111040

Other (OTH) AF: 0.117 AC: 7075 AN: 60358

GnomAD4 genome AF: 0.132 AC: 20148 AN: 152250 Hom.: 1471 Cov.: 33 AF XY: 0.128 AC XY: 9519 AN XY: 74432

African (AFR) AF: 0.194 AC: 8040 AN: 41548

American (AMR) AF: 0.150 AC: 2289 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 637 AN: 3470

East Asian (EAS) AF: 0.0403 AC: 208 AN: 5166

South Asian (SAS) AF: 0.0646 AC: 312 AN: 4830

European-Finnish (FIN) AF: 0.0709 AC: 752 AN: 10610

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7469 AN: 68008

Other (OTH) AF: 0.141 AC: 298 AN: 2112

Alfa AF: 0.128 Hom.: 2196

Bravo AF: 0.143

Asia WGS AF: 0.0680 AC: 237 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 12, 2023

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 24% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.2
DANN	Benign	0.84
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11574790; hg19: chr5-158743846; COSMIC: COSV51455327; COSMIC: COSV51455327;