NM_001374259.2:c.1278G>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001374259.2(IL12RB2):c.1278G>C(p.Gln426His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0439 in 1,595,256 control chromosomes in the GnomAD database, including 1,780 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Synonymous variant affecting the same amino acid position (i.e. Q426Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.054 ( 271 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1509 hom. )

Consequence

IL12RB2
NM_001374259.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0580

Variant links:

Genes affected

IL12RB2 (HGNC:5972): (interleukin 12 receptor subunit beta 2) The protein encoded by this gene is a type I transmembrane protein identified as a subunit of the interleukin 12 receptor complex. The coexpression of this and IL12RB1 proteins was shown to lead to the formation of high-affinity IL12 binding sites and reconstitution of IL12 dependent signaling. The expression of this gene is up-regulated by interferon gamma in Th1 cells, and plays a role in Th1 cell differentiation. The up-regulation of this gene is found to be associated with a number of infectious diseases, such as Crohn's disease and leprosy, which is thought to contribute to the inflammatory response and host defense. Several transcript variants encoding different isoforms and non-protein coding transcripts have been found for this gene. [provided by RefSeq, Apr 2012]

IL12RB2 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=0.0032021403).

BP6

Variant 1-67367844-G-C is Benign according to our data. Variant chr1-67367844-G-C is described in ClinVar as [Benign]. Clinvar id is 1165356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-67367844-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB2	NM_001374259.2 link	c.1278G>C	p.Gln426His	missense_variant	Exon 11 of 17	ENST00000674203.2	NP_001361188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12RB2	ENST00000674203.2 link	c.1278G>C	p.Gln426His	missense_variant	Exon 11 of 17		NM_001374259.2	ENSP00000501329.1		Q99665-1

Frequencies

GnomAD3 genomes

AF:

0.0539

AC:

8192

AN:

152018

Hom.:

269

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0805

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0522

Gnomad ASJ

AF:

0.0879

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0124

Gnomad FIN

AF:

0.0291

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0477

Gnomad OTH

AF:

0.0631

GnomAD3 exomes

AF:

0.0389

AC:

9773

AN:

251432

Hom.:

278

AF XY:

0.0378

AC XY:

5142

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.0787

Gnomad AMR exome

AF:

0.0340

Gnomad ASJ exome

AF:

0.0781

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0138

Gnomad FIN exome

AF:

0.0254

Gnomad NFE exome

AF:

0.0464

Gnomad OTH exome

AF:

0.0468

GnomAD4 exome

AF:

0.0429

AC:

61871

AN:

1443120

Hom.:

1509

Cov.:

AF XY:

0.0423

AC XY:

30424

AN XY:

719346

show subpopulations

Gnomad4 AFR exome

AF:

0.0782

Gnomad4 AMR exome

AF:

0.0370

Gnomad4 ASJ exome

AF:

0.0832

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0147

Gnomad4 FIN exome

AF:

0.0277

Gnomad4 NFE exome

AF:

0.0455

Gnomad4 OTH exome

AF:

0.0441

GnomAD4 genome

AF:

0.0539

AC:

8207

AN:

152136

Hom.:

271

Cov.:

AF XY:

0.0520

AC XY:

3871

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0806

Gnomad4 AMR

AF:

0.0521

Gnomad4 ASJ

AF:

0.0879

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0127

Gnomad4 FIN

AF:

0.0291

Gnomad4 NFE

AF:

0.0477

Gnomad4 OTH

AF:

0.0624

Alfa

AF:

0.0428

Hom.:

147

Bravo

AF:

0.0565

TwinsUK

AF:

0.0512

AC:

190

ALSPAC

AF:

0.0524

AC:

202

ESP6500AA

AF:

0.0785

AC:

346

ESP6500EA

AF:

0.0485

AC:

417

ExAC

AF:

0.0386

AC:

4685

EpiCase

AF:

0.0511

EpiControl

AF:

0.0526

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

IL12RB2-related disorder

Benign:1

Mar 02, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

0.13

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.59

CADD

Benign

8.8

DANN

Benign

0.95

DEOGEN2

Benign

0.064

T;.;.;.;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.66

.;T;T;T;T

MetaRNN

Benign

0.0032

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;M;.;M;M

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.66

N;N;N;N;.

REVEL

Benign

0.051

Sift

Benign

0.14

T;T;T;T;.

Sift4G

Benign

0.069

T;T;T;T;.

Polyphen

0.0020

B;.;.;B;B

Vest4

0.017

MutPred

0.20

Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);

MPC

0.13

ClinPred

0.015

GERP RS

2.0

Varity_R

0.069

gMVP

0.33

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