rs11575934

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_005535.3(IL12RB1):c.641A>G(p.Gln214Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,611,352 control chromosomes in the GnomAD database, including 75,833 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 (★★).

Frequency

Genomes: 𝑓 0.25 ( 5580 hom., cov: 32)

Exomes 𝑓: 0.31 ( 70253 hom. )

Consequence

IL12RB1
NM_005535.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.194

Publications

75 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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005535.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0024283528).

BP6

Variant 19-18075808-T-C is Benign according to our data. Variant chr19-18075808-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB1	NM_005535.3 link	c.641A>G	p.Gln214Arg	missense_variant	Exon 7 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.641A>G	p.Gln214Arg	missense_variant	Exon 7 of 17	1	NM_005535.3	ENSP00000472165.2	P42701-1
IL12RB1	ENST00000600835.6 link	c.641A>G	p.Gln214Arg	missense_variant	Exon 8 of 18	1		ENSP00000470788.1	P42701-1
IL12RB1	ENST00000322153.11 link	c.641A>G	p.Gln214Arg	missense_variant	Exon 7 of 10	1		ENSP00000314425.5	P42701-3

Frequencies

GnomAD3 genomes

AF:

0.254

AC:

38637

AN:

151984

Hom.:

5570

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.246

Gnomad AMR

AF:

0.207

Gnomad ASJ

AF:

0.325

Gnomad EAS

AF:

0.371

Gnomad SAS

AF:

0.238

Gnomad FIN

AF:

0.337

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.320

Gnomad OTH

AF:

0.261

GnomAD2 exomes

AF:

0.277

AC:

69637

AN:

251238

AF XY:

0.283

show subpopulations

Gnomad AFR exome

AF:

0.121

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.336

Gnomad EAS exome

AF:

0.354

Gnomad FIN exome

AF:

0.326

Gnomad NFE exome

AF:

0.321

Gnomad OTH exome

AF:

0.280

GnomAD4 exome

AF:

0.306

AC:

446325

AN:

1459250

Hom.:

70253

Cov.:

AF XY:

0.305

AC XY:

221603

AN XY:

726102

show subpopulations

African (AFR)

AF:

0.119

AC:

3983

AN:

33450

American (AMR)

AF:

0.167

AC:

7458

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.333

AC:

8699

AN:

26120

East Asian (EAS)

AF:

0.385

AC:

15281

AN:

39668

South Asian (SAS)

AF:

0.230

AC:

19837

AN:

86216

European-Finnish (FIN)

AF:

0.325

AC:

17360

AN:

53376

Middle Eastern (MID)

AF:

0.299

AC:

1727

AN:

5768

European-Non Finnish (NFE)

AF:

0.319

AC:

353920

AN:

1109604

Other (OTH)

AF:

0.299

AC:

18060

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

15267

30534

45802

61069

76336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11400

22800

34200

45600

57000

<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:

0.254

AC:

38675

AN:

152102

Hom.:

5580

Cov.:

AF XY:

0.256

AC XY:

19037

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.124

AC:

5162

AN:

41518

American (AMR)

AF:

0.206

AC:

3153

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.325

AC:

1128

AN:

3470

East Asian (EAS)

AF:

0.371

AC:

1919

AN:

5168

South Asian (SAS)

AF:

0.239

AC:

1153

AN:

4822

European-Finnish (FIN)

AF:

0.337

AC:

3563

AN:

10580

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.320

AC:

21744

AN:

67968

Other (OTH)

AF:

0.266

AC:

560

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1458

2916

4374

5832

7290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

404

808

1212

1616

2020

<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:

0.303

Hom.:

17579

Bravo

AF:

0.238

TwinsUK

AF:

0.312

AC:

1158

ALSPAC

AF:

0.323

AC:

1244

ESP6500AA

AF:

0.131

AC:

578

ESP6500EA

AF:

0.316

AC:

2715

ExAC

AF:

0.276

AC:

33563

Asia WGS

AF:

0.322

AC:

1121

AN:

3478

EpiCase

AF:

0.321

EpiControl

AF:

0.316

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 31. Only high quality variants are reported. -

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, no convincing disease association -

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:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 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. -

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.059

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.021

(source)

DANN

Benign

0.11

DEOGEN2

Benign

0.080

T;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.18

.;T;T

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

N;N;N

PhyloP100

-0.19

PrimateAI

Benign

0.24

PROVEAN

Benign

1.0

.;.;N

REVEL

Benign

0.15

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.038

MPC

0.090

ClinPred

0.0042

GERP RS

1.7

Varity_R

0.018

gMVP

0.31

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