chr1-67326816-G-A

Position:

chr1-67326816-G-A

Variant summary

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

The NM_001374259.2(IL12RB2):c.446G>A(p.Arg149Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,613,810 control chromosomes in the GnomAD database, including 41 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 same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0082 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 28 hom. )

Consequence

IL12RB2
NM_001374259.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.214

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=0.0038602352).

BP6

Variant 1-67326816-G-A is Benign according to our data. Variant chr1-67326816-G-A is described in ClinVar as [Benign]. Clinvar id is 774581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-67326816-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00819 (1247/152240) while in subpopulation AFR AF= 0.0227 (942/41566). AF 95% confidence interval is 0.0215. There are 13 homozygotes in gnomad4. There are 581 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB2	NM_001374259.2 linkuse as main transcript	c.446G>A	p.Arg149Gln	missense_variant	5/17	ENST00000674203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB2	ENST00000674203.2 linkuse as main transcript	c.446G>A	p.Arg149Gln	missense_variant	5/17		NM_001374259.2	P1	Q99665-1

Frequencies

GnomAD3 genomes

AF:

0.00816

AC:

1241

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0226

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00760

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.00188

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.00328

AC:

824

AN:

251366

Hom.:

AF XY:

0.00286

AC XY:

388

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.0220

Gnomad AMR exome

AF:

0.00434

Gnomad ASJ exome

AF:

0.000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000915

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00212

Gnomad OTH exome

AF:

0.00587

GnomAD4 exome

AF:

0.00217

AC:

3175

AN:

1461570

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

1527

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.0241

Gnomad4 AMR exome

AF:

0.00481

Gnomad4 ASJ exome

AF:

0.00149

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000974

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00149

Gnomad4 OTH exome

AF:

0.00467

GnomAD4 genome

AF:

0.00819

AC:

1247

AN:

152240

Hom.:

Cov.:

AF XY:

0.00781

AC XY:

581

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0227

Gnomad4 AMR

AF:

0.00759

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00190

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.00325

Hom.:

Bravo

AF:

0.00948

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.0229

AC:

101

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00352

AC:

427

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00289

EpiControl

AF:

0.00356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

IL12RB2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2019

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

0.082

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

5.6

DANN

Benign

0.97

DEOGEN2

Benign

0.20

T;.;.;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.78

.;T;T;T;T

MetaRNN

Benign

0.0039

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.9

L;L;.;L;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.17

PROVEAN

Benign

-1.8

N;N;N;N;.

REVEL

Benign

0.11

Sift

Benign

0.12

T;T;T;T;.

Sift4G

Uncertain

0.019

D;D;D;D;.

Polyphen

0.0050

B;.;.;D;B

Vest4

0.12

MVP

0.31

MPC

0.18

ClinPred

0.016

GERP RS

-2.2

Varity_R

0.047

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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