chr5-159315942-T-G

Variant names:

• chr5-159315942-T-G
• rs3212227
• NM_002187.3:c.*159A>C

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.*159A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 152,312 control chromosomes in the GnomAD database, including 5,876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (5870 hom., cov: 33)
  • Exomes 𝑓: 0.24 (6 hom.)
• Consequence: IL12B NM_002187.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.218
• Publications: 447 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=-0.86).
• BP6: Variant 5-159315942-T-G is Benign according to our data. Variant chr5-159315942-T-G is described in ClinVar as Benign. ClinVar VariationId is 352569.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002187.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12B	NM_002187.3	MANE Select	c.*159A>C		3_prime_UTR	Exon 8 of 8	NP_002178.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12B	ENST00000231228.3	TSL:1 MANE Select	c.*159A>C		3_prime_UTR	Exon 8 of 8	ENSP00000231228.2
	IL12B	ENST00000696751.1		n.*641A>C		non_coding_transcript_exon	Exon 7 of 7	ENSP00000512850.1
	IL12B	ENST00000696750.1		c.*159A>C		3_prime_UTR	Exon 5 of 5	ENSP00000512849.1

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40196 AN: 152050 Hom.: 5863 Cov.: 33

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.285

GnomAD4 exome AF: 0.243 AC: 35 AN: 144 Hom.: 6 Cov.: 0 AF XY: 0.225 AC XY: 18 AN XY: 80

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.246 AC: 32 AN: 130

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.250 AC: 3 AN: 12

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.264 AC: 40228 AN: 152168 Hom.: 5870 Cov.: 33 AF XY: 0.269 AC XY: 19977 AN XY: 74402

African (AFR) AF: 0.337 AC: 13997 AN: 41504

American (AMR) AF: 0.334 AC: 5108 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 579 AN: 3470

East Asian (EAS) AF: 0.465 AC: 2405 AN: 5176

South Asian (SAS) AF: 0.363 AC: 1747 AN: 4808

European-Finnish (FIN) AF: 0.179 AC: 1897 AN: 10592

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13626 AN: 68004

Other (OTH) AF: 0.287 AC: 607 AN: 2114

Alfa AF: 0.233 Hom.: 7369

Bravo AF: 0.281

Asia WGS AF: 0.432 AC: 1497 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.46
PhyloP100		-0.22
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: rs3212227; hg19: chr5-158742950;