19-18069603-C-G

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.1132G>C(p.Gly378Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,612,144 control chromosomes in the GnomAD database, including 77,178 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G378W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.28 ( 6170 hom., cov: 33)

Exomes 𝑓: 0.31 ( 71008 hom. )

Consequence

IL12RB1
NM_005535.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.86

Publications

60 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=0.0019493997).

BP6

Variant 19-18069603-C-G is Benign according to our data. Variant chr19-18069603-C-G is described in ClinVar as Benign. ClinVar VariationId is 328587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB1	NM_005535.3 link	c.1132G>C	p.Gly378Arg	missense_variant	Exon 10 of 17	ENST00000593993.7	NP_005526.1	P42701-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7 link	c.1132G>C	p.Gly378Arg	missense_variant	Exon 10 of 17	1	NM_005535.3	ENSP00000472165.2		P42701-1
IL12RB1	ENST00000600835.6 link	c.1132G>C	p.Gly378Arg	missense_variant	Exon 11 of 18	1		ENSP00000470788.1		P42701-1

Frequencies

GnomAD3 genomes

AF:

0.277

AC:

42056

AN:

152042

Hom.:

6156

Cov.:

show subpopulations

Gnomad AFR

AF:

0.201

Gnomad AMI

AF:

0.250

Gnomad AMR

AF:

0.216

Gnomad ASJ

AF:

0.325

Gnomad EAS

AF:

0.372

Gnomad SAS

AF:

0.238

Gnomad FIN

AF:

0.337

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.321

Gnomad OTH

AF:

0.277

GnomAD2 exomes

AF:

0.282

AC:

69853

AN:

247766

AF XY:

0.286

show subpopulations

Gnomad AFR exome

AF:

0.196

Gnomad AMR exome

AF:

0.165

Gnomad ASJ exome

AF:

0.336

Gnomad EAS exome

AF:

0.355

Gnomad FIN exome

AF:

0.322

Gnomad NFE exome

AF:

0.321

Gnomad OTH exome

AF:

0.282

GnomAD4 exome

AF:

0.309

AC:

450439

AN:

1459984

Hom.:

71008

Cov.:

AF XY:

0.307

AC XY:

223346

AN XY:

726364

show subpopulations

African (AFR)

AF:

0.196

AC:

6561

AN:

33474

American (AMR)

AF:

0.171

AC:

7633

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.333

AC:

8704

AN:

26128

East Asian (EAS)

AF:

0.388

AC:

15389

AN:

39690

South Asian (SAS)

AF:

0.231

AC:

19888

AN:

86242

European-Finnish (FIN)

AF:

0.322

AC:

16802

AN:

52136

Middle Eastern (MID)

AF:

0.300

AC:

1731

AN:

5762

European-Non Finnish (NFE)

AF:

0.320

AC:

355308

AN:

1111490

Other (OTH)

AF:

0.305

AC:

18423

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

15605

31210

46815

62420

78025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11498

22996

34494

45992

57490

<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:

0.277

AC:

42101

AN:

152160

Hom.:

6170

Cov.:

AF XY:

0.278

AC XY:

20644

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.201

AC:

8345

AN:

41532

American (AMR)

AF:

0.216

AC:

3292

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.325

AC:

1130

AN:

3472

East Asian (EAS)

AF:

0.372

AC:

1920

AN:

5168

South Asian (SAS)

AF:

0.239

AC:

1155

AN:

4834

European-Finnish (FIN)

AF:

0.337

AC:

3569

AN:

10576

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.321

AC:

21794

AN:

67982

Other (OTH)

AF:

0.281

AC:

595

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1606

3213

4819

6426

8032

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

438

876

1314

1752

2190

<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:

0.302

Hom.:

4820

Bravo

AF:

0.264

TwinsUK

AF:

0.312

AC:

1157

ALSPAC

AF:

0.322

AC:

1242

ESP6500AA

AF:

0.197

AC:

796

ESP6500EA

AF:

0.309

AC:

2582

ExAC

AF:

0.283

AC:

34291

Asia WGS

AF:

0.327

AC:

1137

AN:

3478

EpiCase

AF:

0.322

EpiControl

AF:

0.315

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

Aug 19, 2021

Genome-Nilou Lab

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. -

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, variant associated with tuberculosis susceptibility -

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.0050

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.085

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.40

.;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

PhyloP100

-1.9

PrimateAI

Benign

0.23

Sift4G

Benign

0.35

T;T

Polyphen

0.0030

B;B

Vest4

0.043

MutPred

0.11

Gain of solvent accessibility (P = 0.1319);Gain of solvent accessibility (P = 0.1319);

MPC

0.10

ClinPred

0.000035

GERP RS

-4.1

Varity_R

0.029

gMVP

0.34

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