chr5-159323135-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002187.3(IL12B):c.283G>A(p.Glu95Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00031 in 1,614,144 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 3 hom. )

Consequence

IL12B
NM_002187.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -1.97

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053356886).

BP6

Variant 5-159323135-C-T is Benign according to our data. Variant chr5-159323135-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541814.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00139 (212/152306) while in subpopulation AFR AF= 0.00498 (207/41554). AF 95% confidence interval is 0.00443. There are 0 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12B	NM_002187.3 link	c.283G>A	p.Glu95Lys	missense_variant	Exon 3 of 8	ENST00000231228.3	NP_002178.2	P29460

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IL12B	ENST00000231228.3 link	c.283G>A	p.Glu95Lys	missense_variant	Exon 3 of 8	1	NM_002187.3	ENSP00000231228.2	P29460
IL12B	ENST00000696750.1 link	c.-148-2615G>A		intron_variant	Intron 1 of 4			ENSP00000512849.1	A0A8Q3WML5
IL12B	ENST00000696751.1 link	n.283G>A		non_coding_transcript_exon_variant	Exon 3 of 7			ENSP00000512850.1	A0A8Q3SJ12
ENSG00000249738	ENST00000521472.6 link	n.290-2399C>T		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

212

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00500

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000378

AC:

AN:

251394

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00523

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000197

AC:

288

AN:

1461838

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

132

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00675

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.00139

AC:

212

AN:

152306

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00498

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000355

Hom.:

Bravo

AF:

0.00181

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency

Uncertain:1Benign:2

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IL12B NM_002187.2 exon 3 p.Glu95Lys (c.283G>A): This variant has not been reported in the literature but is present in 0.5% (131/24968) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-158750143-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:541841). This variant amino acid Lysine (Lys) is present in >15 species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

IL12B-related disorder

Benign:1

Nov 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.0020

DANN

Benign

0.95

DEOGEN2

Benign

0.19

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.55

M_CAP

Benign

0.0039

MetaRNN

Benign

0.0053

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.72

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

REVEL

Benign

0.010

Sift

Benign

0.19

Sift4G

Benign

0.32

Polyphen

0.047

Vest4

0.15

MVP

0.35

MPC

0.34

ClinPred

0.0062

GERP RS

0.21

Varity_R

0.16

gMVP

0.64

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

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