19-18063921-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005535.3(IL12RB1):c.1573G>A(p.Ala525Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0052 in 1,613,430 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A525A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0065 ( 19 hom., cov: 30)

Exomes 𝑓: 0.0051 ( 148 hom. )

Consequence

IL12RB1
NM_005535.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.439

Publications

22 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=0.0067195).

BP6

Variant 19-18063921-C-T is Benign according to our data. Variant chr19-18063921-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00652 (992/152208) while in subpopulation EAS AF = 0.0454 (234/5156). AF 95% confidence interval is 0.0406. There are 19 homozygotes in GnomAd4. There are 537 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB1	NM_005535.3 link	c.1573G>A	p.Ala525Thr	missense_variant	Exon 13 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.1573G>A	p.Ala525Thr	missense_variant	Exon 13 of 17	1	NM_005535.3	ENSP00000472165.2		P42701-1
IL12RB1	ENST00000600835.6 link	c.1573G>A	p.Ala525Thr	missense_variant	Exon 14 of 18	1		ENSP00000470788.1		P42701-1

Frequencies

GnomAD3 genomes

AF:

0.00646

AC:

983

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00891

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.0457

Gnomad SAS

AF:

0.0414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.0111

AC:

2755

AN:

248232

AF XY:

0.0123

show subpopulations

Gnomad AFR exome

AF:

0.00937

Gnomad AMR exome

AF:

0.00157

Gnomad ASJ exome

AF:

0.0148

Gnomad EAS exome

AF:

0.0532

Gnomad FIN exome

AF:

0.0000931

Gnomad NFE exome

AF:

0.00165

Gnomad OTH exome

AF:

0.00880

GnomAD4 exome

AF:

0.00506

AC:

7397

AN:

1461222

Hom.:

148

Cov.:

AF XY:

0.00621

AC XY:

4512

AN XY:

726904

show subpopulations

African (AFR)

AF:

0.00938

AC:

314

AN:

33474

American (AMR)

AF:

0.00172

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0132

AC:

345

AN:

26114

East Asian (EAS)

AF:

0.0398

AC:

1581

AN:

39694

South Asian (SAS)

AF:

0.0401

AC:

3459

AN:

86204

European-Finnish (FIN)

AF:

0.0000563

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.0174

AC:

100

AN:

5760

European-Non Finnish (NFE)

AF:

0.000872

AC:

969

AN:

1111608

Other (OTH)

AF:

0.00910

AC:

549

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

375

751

1126

1502

1877

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<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:

0.00652

AC:

992

AN:

152208

Hom.:

Cov.:

AF XY:

0.00722

AC XY:

537

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.00898

AC:

373

AN:

41534

American (AMR)

AF:

0.00229

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3470

East Asian (EAS)

AF:

0.0454

AC:

234

AN:

5156

South Asian (SAS)

AF:

0.0409

AC:

197

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00113

AC:

AN:

68020

Other (OTH)

AF:

0.0147

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

103

154

206

257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00540

Hom.:

Bravo

AF:

0.00655

ESP6500AA

AF:

0.00937

AC:

ESP6500EA

AF:

0.00142

AC:

ExAC

AF:

0.0113

AC:

1362

Asia WGS

AF:

0.0650

AC:

226

AN:

3478

EpiCase

AF:

0.00207

EpiControl

AF:

0.00225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 22, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 18, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31367980) -

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

- -

Jan 12, 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. -

Apr 20, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.76

.;T

MetaRNN

Benign

0.0067

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

M;M

PhyloP100

0.44

PrimateAI

Benign

0.37

Sift4G

Uncertain

0.016

D;D

Polyphen

1.0

D;D

Vest4

0.064

MPC

0.21

ClinPred

0.0087

GERP RS

2.1

Varity_R

0.049

gMVP

0.28

Mutation Taster

=81/19

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