rs2307153

Positions:

Variant summary

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

The NM_001374259.2(IL12RB2):c.1394G>A(p.Gly465Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,610,054 control chromosomes in the GnomAD database, including 342 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 0.015 ( 21 hom., cov: 32)

Exomes 𝑓: 0.019 ( 321 hom. )

Consequence

IL12RB2
NM_001374259.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.840

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=0.003908336).

BP6

Variant 1-67367960-G-A is Benign according to our data. Variant chr1-67367960-G-A is described in ClinVar as [Benign]. Clinvar id is 1166571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-67367960-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0146 (2229/152266) while in subpopulation NFE AF= 0.0226 (1539/68010). AF 95% confidence interval is 0.0217. There are 21 homozygotes in gnomad4. There are 1067 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL12RB2	NM_001374259.2 linkuse as main transcript	c.1394G>A	p.Gly465Asp	missense_variant	11/17	ENST00000674203.2	NP_001361188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL12RB2	ENST00000674203.2 linkuse as main transcript	c.1394G>A	p.Gly465Asp	missense_variant	11/17		NM_001374259.2	ENSP00000501329	P1	Q99665-1

Frequencies

GnomAD3 genomes

AF:

0.0147

AC:

2229

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00408

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0159

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0225

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0226

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.0139

AC:

3498

AN:

251434

Hom.:

AF XY:

0.0140

AC XY:

1902

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00326

Gnomad AMR exome

AF:

0.00971

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.0218

Gnomad NFE exome

AF:

0.0220

Gnomad OTH exome

AF:

0.0145

GnomAD4 exome

AF:

0.0195

AC:

28393

AN:

1457788

Hom.:

321

Cov.:

AF XY:

0.0190

AC XY:

13804

AN XY:

725540

show subpopulations

Gnomad4 AFR exome

AF:

0.00353

Gnomad4 AMR exome

AF:

0.0108

Gnomad4 ASJ exome

AF:

0.00234

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000592

Gnomad4 FIN exome

AF:

0.0222

Gnomad4 NFE exome

AF:

0.0229

Gnomad4 OTH exome

AF:

0.0178

GnomAD4 genome

AF:

0.0146

AC:

2229

AN:

152266

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1067

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00407

Gnomad4 AMR

AF:

0.0159

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0225

Gnomad4 NFE

AF:

0.0226

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0195

Hom.:

Bravo

AF:

0.0137

TwinsUK

AF:

0.0256

AC:

ALSPAC

AF:

0.0205

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0190

AC:

163

ExAC

AF:

0.0141

AC:

1711

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0206

EpiControl

AF:

0.0198

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

IL12RB2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 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

0.069

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.14

DANN

Benign

0.27

DEOGEN2

Benign

0.069

T;.;.;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.52

.;T;T;T;T

MetaRNN

Benign

0.0039

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.9

M;M;.;M;M

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.5

N;N;N;N;.

REVEL

Benign

0.038

Sift

Benign

0.13

T;T;T;T;.

Sift4G

Uncertain

0.0070

D;D;D;D;.

Polyphen

0.0020

B;.;.;B;B

Vest4

0.018

MPC

0.18

ClinPred

0.012

GERP RS

-3.2

Varity_R

0.096

gMVP

0.48

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