Genetic Variant IL12B:p.Thr169Lys (chr5-159320497-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_002187.3(IL12B):c.506C>A(p.Thr169Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T169M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

IL12B
NM_002187.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.67

Publications

2 publications found

Variant links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

IL12B links:

IL12B-AS1 (HGNC:58156):

IL12B-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.801

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12B	NM_002187.3	MANE Select	c.506C>A	p.Thr169Lys	missense	Exon 5 of 8	NP_002178.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL12B	ENST00000231228.3	TSL:1 MANE Select	c.506C>A	p.Thr169Lys	missense	Exon 5 of 8	ENSP00000231228.2	P29460
IL12B	ENST00000696750.1		c.-125C>A		5_prime_UTR	Exon 2 of 5	ENSP00000512849.1	A0A8Q3WML5
IL12B	ENST00000696751.1		n.*1C>A		non_coding_transcript_exon	Exon 4 of 7	ENSP00000512850.1	A0A8Q3SJ12

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.32

Eigen

Benign

0.083

Eigen_PC

Benign

0.0024

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.80

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.8

PhyloP100

1.7

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.8

REVEL

Benign

0.27

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0030

Polyphen

0.98

Vest4

0.51

MutPred

0.66

Gain of methylation at T169 (P = 5e-04)

MVP

0.79

MPC

0.97

ClinPred

0.92

GERP RS

4.4

Varity_R

0.32

gMVP

0.65

Mutation Taster

=82/18

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over