5-159323005-T-C

Variant names:

• chr5-159323005-T-C
• rs2288831
• NM_002187.3:c.364+49A>G

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.364+49A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,571,908 control chromosomes in the GnomAD database, including 46,246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.27 (5925 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40321 hom.)
• Consequence: IL12B NM_002187.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.676
• Publications: 29 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=-0.87).
• BP6: Variant 5-159323005-T-C is Benign according to our data. Variant chr5-159323005-T-C is described in ClinVar as Benign. ClinVar VariationId is 2628167.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12B	NM_002187.3	c.364+49A>G		intron_variant	Intron 3 of 7	ENST00000231228.3	NP_002178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12B	ENST00000231228.3	c.364+49A>G		intron_variant	Intron 3 of 7	1	NM_002187.3	ENSP00000231228.2

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40313 AN: 151944 Hom.: 5919 Cov.: 32

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.286

GnomAD2 exomes AF: 0.276 AC: 67883 AN: 245918 AF XY: 0.273

Gnomad AFR exome AF: 0.342

Gnomad AMR exome AF: 0.390

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.466

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.251

GnomAD4 exome AF: 0.225 AC: 319858 AN: 1419846 Hom.: 40321 Cov.: 26 AF XY: 0.228 AC XY: 161638 AN XY: 708682

African (AFR) AF: 0.348 AC: 11294 AN: 32470

American (AMR) AF: 0.381 AC: 16980 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 4570 AN: 25868

East Asian (EAS) AF: 0.508 AC: 20055 AN: 39472

South Asian (SAS) AF: 0.350 AC: 29782 AN: 85052

European-Finnish (FIN) AF: 0.179 AC: 9552 AN: 53216

Middle Eastern (MID) AF: 0.280 AC: 1466 AN: 5236

European-Non Finnish (NFE) AF: 0.197 AC: 211722 AN: 1075080

Other (OTH) AF: 0.245 AC: 14437 AN: 58910

GnomAD4 genome AF: 0.265 AC: 40343 AN: 152062 Hom.: 5925 Cov.: 32 AF XY: 0.269 AC XY: 20019 AN XY: 74306

African (AFR) AF: 0.340 AC: 14074 AN: 41444

American (AMR) AF: 0.334 AC: 5097 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 580 AN: 3472

East Asian (EAS) AF: 0.475 AC: 2457 AN: 5174

South Asian (SAS) AF: 0.362 AC: 1742 AN: 4814

European-Finnish (FIN) AF: 0.178 AC: 1884 AN: 10578

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.201 AC: 13642 AN: 67988

Other (OTH) AF: 0.287 AC: 606 AN: 2114

Alfa AF: 0.232 Hom.: 5890

Bravo AF: 0.282

Asia WGS AF: 0.438 AC: 1518 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 53% of patients studied by a panel of primary immunodeficiencies. Number of patients: 51. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.63
DANN	Benign	0.57
PhyloP100		-0.68
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: rs2288831; hg19: chr5-158750013; COSMIC: COSV51455199; COSMIC: COSV51455199;