rs3213099

Positions:

• chr5-159320528-C-G
• chr5-159320528-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002187.3(IL12B):​c.483-8G>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,611,924 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (76 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (58 hom.)
• Consequence: IL12B NM_002187.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002838
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.233

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 5-159320528-C-G is Benign according to our data. Variant chr5-159320528-C-G is described in ClinVar as [Benign]. Clinvar id is 352576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL12B	NM_002187.3	c.483-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000231228.3	NP_002178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL12B	ENST00000231228.3	c.483-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002187.3	ENSP00000231228	P1
IL12B	ENST00000696750.1	c.-148-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				ENSP00000512849
IL12B	ENST00000696751.1	c.365-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant				ENSP00000512850
	ENST00000521472.6	n.290-5006C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2477 AN: 152178 Hom.: 76 Cov.: 32

Gnomad AFR AF: 0.0568

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00423 AC: 1061 AN: 250808 Hom.: 33 AF XY: 0.00292 AC XY: 396 AN XY: 135574

Gnomad AFR exome AF: 0.0578

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00167 AC: 2436 AN: 1459628 Hom.: 58 Cov.: 30 AF XY: 0.00141 AC XY: 1022 AN XY: 726286

Gnomad4 AFR exome AF: 0.0579

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000145

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.0163 AC: 2478 AN: 152296 Hom.: 76 Cov.: 32 AF XY: 0.0153 AC XY: 1142 AN XY: 74470

Gnomad4 AFR AF: 0.0567

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00452 Hom.: 2

Bravo AF: 0.0180

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.5
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.026
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

Publications

LitVar

Other links and lift over

dbSNP: rs3213099; hg19: chr5-158747536;