rs74644143

Positions:

chr5-159318842-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_002187.3(IL12B):c.749G>A(p.Arg250Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

IL12B
NM_002187.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.0940

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0034862459).

BP6

Variant 5-159318842-C-T is Benign according to our data. Variant chr5-159318842-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541815.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00185 (282/152214) while in subpopulation AFR AF= 0.0065 (270/41538). AF 95% confidence interval is 0.00586. There are 0 homozygotes in gnomad4. There are 108 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12B	NM_002187.3 linkuse as main transcript	c.749G>A	p.Arg250Gln	missense_variant	6/8	ENST00000231228.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
IL12B	ENST00000231228.3 linkuse as main transcript	c.749G>A	p.Arg250Gln	missense_variant	6/8	1	NM_002187.3	P1
IL12B	ENST00000696750.1 linkuse as main transcript	c.119G>A	p.Arg40Gln	missense_variant	3/5
IL12B	ENST00000696751.1 linkuse as main transcript	c.*244G>A		3_prime_UTR_variant, NMD_transcript_variant	5/7
	ENST00000521472.6 linkuse as main transcript	n.290-6692C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00186

AC:

283

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00654

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000588

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000461

AC:

116

AN:

251406

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00664

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000177

AC:

258

AN:

1461744

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

102

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00660

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.00185

AC:

282

AN:

152214

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

108

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00650

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000314

Hom.:

Bravo

AF:

0.00198

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000585

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	IL12B NM_002187.2 exon 6 p.Arg250Gln (c.749G>A): This variant has not been reported in the literature and is present in 0.6% (167/24966) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/5-158745850-C-T). This variant is present in ClinVar (Variation ID:541815). This variant amino acid Glutamine (Gln) is present in several species including multiple mammals, and it 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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.097

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.73

M_CAP

Benign

0.0054

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

PrimateAI

Benign

0.20

PROVEAN

Benign

0.080

REVEL

Benign

0.073

Sift

Benign

0.23

Sift4G

Benign

0.30

Polyphen

0.0080

Vest4

0.11

MVP

0.51

MPC

0.34

ClinPred

0.012

GERP RS

0.39

Varity_R

0.33

gMVP

0.26

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