NM_002187.3:c.892G>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002187.3(IL12B):c.892G>T(p.Val298Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,614,030 control chromosomes in the GnomAD database, including 649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 40 hom., cov: 33)

Exomes 𝑓: 0.027 ( 609 hom. )

Consequence

IL12B
NM_002187.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.06

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 links:

ENSG00000249738 (HGNC:58156):

ENSG00000249738 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036674142).

BP6

Variant 5-159316780-C-A is Benign according to our data. Variant chr5-159316780-C-A is described in ClinVar as [Benign]. Clinvar id is 352572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-159316780-C-A is described in Lovd as [Benign]. Variant chr5-159316780-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0212 (3224/152302) while in subpopulation NFE AF= 0.0304 (2067/68028). AF 95% confidence interval is 0.0293. There are 40 homozygotes in gnomad4. There are 1578 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12B	NM_002187.3 link	c.892G>T	p.Val298Phe	missense_variant	Exon 7 of 8	ENST00000231228.3	NP_002178.2	P29460

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12B	ENST00000231228.3 link	c.892G>T	p.Val298Phe	missense_variant	Exon 7 of 8	1	NM_002187.3	ENSP00000231228.2		P29460

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3224

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00610

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0289

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0291

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0304

Gnomad OTH

AF:

0.0244

GnomAD3 exomes

AF:

0.0207

AC:

5150

AN:

248422

Hom.:

AF XY:

0.0203

AC XY:

2721

AN XY:

134366

show subpopulations

Gnomad AFR exome

AF:

0.00527

Gnomad AMR exome

AF:

0.0209

Gnomad ASJ exome

AF:

0.0152

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00242

Gnomad FIN exome

AF:

0.0303

Gnomad NFE exome

AF:

0.0300

Gnomad OTH exome

AF:

0.0207

GnomAD4 exome

AF:

0.0273

AC:

39960

AN:

1461728

Hom.:

609

Cov.:

AF XY:

0.0263

AC XY:

19159

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.00508

Gnomad4 AMR exome

AF:

0.0217

Gnomad4 ASJ exome

AF:

0.0164

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00254

Gnomad4 FIN exome

AF:

0.0290

Gnomad4 NFE exome

AF:

0.0316

Gnomad4 OTH exome

AF:

0.0236

GnomAD4 genome

AF:

0.0212

AC:

3224

AN:

152302

Hom.:

Cov.:

AF XY:

0.0212

AC XY:

1578

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00609

Gnomad4 AMR

AF:

0.0288

Gnomad4 ASJ

AF:

0.0159

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0291

Gnomad4 NFE

AF:

0.0304

Gnomad4 OTH

AF:

0.0241

Alfa

AF:

0.0286

Hom.:

162

Bravo

AF:

0.0210

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0298

AC:

115

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.0303

AC:

261

ExAC

AF:

0.0205

AC:

2485

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0286

EpiControl

AF:

0.0313

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency

Benign:2

Jan 12, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.56

MutationAssessor

Pathogenic

3.2

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.13

Sift

Uncertain

0.021

Sift4G

Uncertain

0.0050

Polyphen

0.98

Vest4

0.24

MPC

0.90

ClinPred

0.066

GERP RS

5.7

Varity_R

0.64

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over