rs11575926

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005535.3(IL12RB1):c.467G>A(p.Arg156His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,597,014 control chromosomes in the GnomAD database, including 22,380 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.12 ( 1420 hom., cov: 31)

Exomes 𝑓: 0.16 ( 20960 hom. )

Consequence

IL12RB1
NM_005535.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.41

Publications

35 publications found

Variant links:

Genes affected

IL12RB1 (HGNC:5971): (interleukin 12 receptor subunit beta 1) The protein encoded by this gene is a type I transmembrane protein that belongs to the hemopoietin receptor superfamily. This protein binds to interleukine 12 (IL12) with a low affinity, and is thought to be a part of IL12 receptor complex. This protein forms a disulfide-linked oligomer, which is required for its IL12 binding activity. The coexpression of this and IL12RB2 proteins was shown to lead to the formation of high-affinity IL12 binding sites and reconstitution of IL12 dependent signaling. Mutations in this gene impair the development of interleukin-17-producing T lymphocytes and result in increased susceptibility to mycobacterial and Salmonella infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

IL12RB1 Gene-Disease associations (from GenCC):

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

IL12RB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002072394).

BP6

Variant 19-18077598-C-T is Benign according to our data. Variant chr19-18077598-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB1	NM_005535.3 link	c.467G>A	p.Arg156His	missense_variant	Exon 5 of 17	ENST00000593993.7	NP_005526.1	P42701-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IL12RB1	ENST00000593993.7 link	c.467G>A	p.Arg156His	missense_variant	Exon 5 of 17	1	NM_005535.3	ENSP00000472165.2	P42701-1
IL12RB1	ENST00000600835.6 link	c.467G>A	p.Arg156His	missense_variant	Exon 6 of 18	1		ENSP00000470788.1	P42701-1
IL12RB1	ENST00000322153.11 link	c.467G>A	p.Arg156His	missense_variant	Exon 5 of 10	1		ENSP00000314425.5	P42701-3

Frequencies

GnomAD3 genomes

AF:

0.120

AC:

18197

AN:

152004

Hom.:

1419

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0294

Gnomad AMI

AF:

0.0934

Gnomad AMR

AF:

0.0919

Gnomad ASJ

AF:

0.190

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.0796

Gnomad FIN

AF:

0.198

Gnomad MID

AF:

0.102

Gnomad NFE

AF:

0.178

Gnomad OTH

AF:

0.123

GnomAD2 exomes

AF:

0.127

AC:

31791

AN:

250760

AF XY:

0.130

show subpopulations

Gnomad AFR exome

AF:

0.0283

Gnomad AMR exome

AF:

0.0677

Gnomad ASJ exome

AF:

0.192

Gnomad EAS exome

AF:

0.000761

Gnomad FIN exome

AF:

0.188

Gnomad NFE exome

AF:

0.174

Gnomad OTH exome

AF:

0.137

GnomAD4 exome

AF:

0.163

AC:

234981

AN:

1444892

Hom.:

20960

Cov.:

AF XY:

0.161

AC XY:

115887

AN XY:

719732

show subpopulations

African (AFR)

AF:

0.0236

AC:

783

AN:

33158

American (AMR)

AF:

0.0695

AC:

3103

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.191

AC:

4969

AN:

26032

East Asian (EAS)

AF:

0.000530

AC:

AN:

39618

South Asian (SAS)

AF:

0.0819

AC:

7031

AN:

85896

European-Finnish (FIN)

AF:

0.184

AC:

9821

AN:

53378

Middle Eastern (MID)

AF:

0.144

AC:

827

AN:

5736

European-Non Finnish (NFE)

AF:

0.182

AC:

199374

AN:

1096588

Other (OTH)

AF:

0.151

AC:

9052

AN:

59812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

8817

17634

26450

35267

44084

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6776

13552

20328

27104

33880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.120

AC:

18201

AN:

152122

Hom.:

1420

Cov.:

AF XY:

0.119

AC XY:

8830

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.0293

AC:

1216

AN:

41532

American (AMR)

AF:

0.0918

AC:

1402

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

660

AN:

3472

East Asian (EAS)

AF:

0.000966

AC:

AN:

5176

South Asian (SAS)

AF:

0.0810

AC:

391

AN:

4830

European-Finnish (FIN)

AF:

0.198

AC:

2088

AN:

10570

Middle Eastern (MID)

AF:

0.113

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.178

AC:

12064

AN:

67958

Other (OTH)

AF:

0.122

AC:

257

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

799

1598

2397

3196

3995

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

208

416

624

832

1040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.147

Hom.:

1166

Bravo

AF:

0.108

TwinsUK

AF:

0.179

AC:

665

ALSPAC

AF:

0.189

AC:

729

ESP6500AA

AF:

0.0359

AC:

158

ESP6500EA

AF:

0.174

AC:

1494

ExAC

AF:

0.126

AC:

15244

Asia WGS

AF:

0.0350

AC:

123

AN:

3478

EpiCase

AF:

0.174

EpiControl

AF:

0.167

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Immunodeficiency 27A

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 09, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.16

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.21

T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0080

LIST_S2

Benign

0.71

.;T;T

MetaRNN

Benign

0.0021

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L;L

PhyloP100

-1.4

PrimateAI

Benign

0.23

PROVEAN

Benign

-2.1

.;.;N

REVEL

Benign

0.13

Sift4G

Benign

0.093

T;T;T

Polyphen

0.014

B;B;B

Vest4

0.039

MPC

0.11

ClinPred

0.0016

GERP RS

-7.8

Varity_R

0.021

gMVP

0.28

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over