19-18059998-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_005535.3(IL12RB1):c.1879G>A(p.Glu627Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000592 in 1,600,834 control chromosomes in the GnomAD database, including 1 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 1 hom. )

Consequence

IL12RB1
NM_005535.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0750

Publications

5 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005658984).

BP6

Variant 19-18059998-C-T is Benign according to our data. Variant chr19-18059998-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 328576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000453 (69/152310) while in subpopulation SAS AF = 0.00311 (15/4828). AF 95% confidence interval is 0.00191. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB1	NM_005535.3 link	c.1879G>A	p.Glu627Lys	missense_variant	Exon 16 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.1879G>A	p.Glu627Lys	missense_variant	Exon 16 of 17	1	NM_005535.3	ENSP00000472165.2		P42701-1
IL12RB1	ENST00000600835.6 link	c.1879G>A	p.Glu627Lys	missense_variant	Exon 17 of 18	1		ENSP00000470788.1		P42701-1

Frequencies

GnomAD3 genomes

AF:

0.000440

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000831

AC:

199

AN:

239360

AF XY:

0.00103

show subpopulations

Gnomad AFR exome

AF:

0.000140

Gnomad AMR exome

AF:

0.000150

Gnomad ASJ exome

AF:

0.000723

Gnomad EAS exome

AF:

0.0000570

Gnomad FIN exome

AF:

0.000568

Gnomad NFE exome

AF:

0.000766

Gnomad OTH exome

AF:

0.00221

GnomAD4 exome

AF:

0.000607

AC:

879

AN:

1448524

Hom.:

Cov.:

AF XY:

0.000709

AC XY:

511

AN XY:

720582

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33156

American (AMR)

AF:

0.000137

AC:

AN:

43886

Ashkenazi Jewish (ASJ)

AF:

0.000813

AC:

AN:

25830

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39520

South Asian (SAS)

AF:

0.00251

AC:

213

AN:

84788

European-Finnish (FIN)

AF:

0.000678

AC:

AN:

53060

Middle Eastern (MID)

AF:

0.00261

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.000501

AC:

552

AN:

1102640

Other (OTH)

AF:

0.000568

AC:

AN:

59898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

121

181

242

302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000453

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41564

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00311

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000743

Hom.:

Bravo

AF:

0.000518

ESP6500AA

AF:

0.000252

AC:

ESP6500EA

AF:

0.000361

AC:

ExAC

AF:

0.000993

AC:

120

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

IL12RB1-related disorder

Benign:1

Aug 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

0.073

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

7.7

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.46

.;T

M_CAP

Benign

0.050

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.83

L;L

PhyloP100

-0.075

PrimateAI

Benign

0.27

Sift4G

Uncertain

0.022

D;D

Polyphen

0.89

P;P

Vest4

0.068

MVP

0.84

MPC

0.10

ClinPred

0.033

GERP RS

1.4

Varity_R

0.046

gMVP

0.11

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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