rs375947

Positions:

chr19-18069641-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000593993.7(IL12RB1):c.1094T>C(p.Met365Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,612,186 control chromosomes in the GnomAD database, including 78,539 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 6814 hom., cov: 33)

Exomes 𝑓: 0.31 ( 71725 hom. )

Consequence

IL12RB1
ENST00000593993.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.948

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004220456).

BP6

Variant 19-18069641-A-G is Benign according to our data. Variant chr19-18069641-A-G is described in ClinVar as [Benign]. Clinvar id is 328588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18069641-A-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
IL12RB1	NM_005535.3 linkuse as main transcript	c.1094T>C	p.Met365Thr	missense_variant	10/17	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7 linkuse as main transcript	c.1094T>C	p.Met365Thr	missense_variant	10/17	1	NM_005535.3	ENSP00000472165	P1	P42701-1
IL12RB1	ENST00000600835.6 linkuse as main transcript	c.1094T>C	p.Met365Thr	missense_variant	11/18	1		ENSP00000470788	P1	P42701-1

Frequencies

GnomAD3 genomes

AF:

0.295

AC:

44790

AN:

152018

Hom.:

6797

Cov.:

show subpopulations

Gnomad AFR

AF:

0.263

Gnomad AMI

AF:

0.250

Gnomad AMR

AF:

0.224

Gnomad ASJ

AF:

0.326

Gnomad EAS

AF:

0.372

Gnomad SAS

AF:

0.239

Gnomad FIN

AF:

0.337

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.321

Gnomad OTH

AF:

0.291

GnomAD3 exomes

AF:

0.287

AC:

71468

AN:

248808

Hom.:

10792

AF XY:

0.290

AC XY:

39171

AN XY:

135036

show subpopulations

Gnomad AFR exome

AF:

0.262

Gnomad AMR exome

AF:

0.168

Gnomad ASJ exome

AF:

0.337

Gnomad EAS exome

AF:

0.355

Gnomad SAS exome

AF:

0.227

Gnomad FIN exome

AF:

0.324

Gnomad NFE exome

AF:

0.322

Gnomad OTH exome

AF:

0.284

GnomAD4 exome

AF:

0.310

AC:

453258

AN:

1460050

Hom.:

71725

Cov.:

AF XY:

0.309

AC XY:

224601

AN XY:

726386

show subpopulations

Gnomad4 AFR exome

AF:

0.261

Gnomad4 AMR exome

AF:

0.174

Gnomad4 ASJ exome

AF:

0.333

Gnomad4 EAS exome

AF:

0.388

Gnomad4 SAS exome

AF:

0.231

Gnomad4 FIN exome

AF:

0.323

Gnomad4 NFE exome

AF:

0.320

Gnomad4 OTH exome

AF:

0.309

GnomAD4 genome

AF:

0.295

AC:

44839

AN:

152136

Hom.:

6814

Cov.:

AF XY:

0.295

AC XY:

21934

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.263

Gnomad4 AMR

AF:

0.223

Gnomad4 ASJ

AF:

0.326

Gnomad4 EAS

AF:

0.372

Gnomad4 SAS

AF:

0.239

Gnomad4 FIN

AF:

0.337

Gnomad4 NFE

AF:

0.321

Gnomad4 OTH

AF:

0.295

Alfa

AF:

0.318

Hom.:

16403

Bravo

AF:

0.284

TwinsUK

AF:

0.312

AC:

1157

ALSPAC

AF:

0.322

AC:

1242

ESP6500AA

AF:

0.258

AC:

1071

ESP6500EA

AF:

0.311

AC:

2613

ExAC

AF:

0.289

AC:

34951

Asia WGS

AF:

0.330

AC:

1149

AN:

3478

EpiCase

AF:

0.322

EpiControl

AF:

0.316

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.017

DANN

Benign

0.26

DEOGEN2

Benign

0.073

T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.19

.;T

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.0

N;N

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.0060

MPC

0.097

ClinPred

0.0015

GERP RS

-4.5

Varity_R

0.042

gMVP

0.32

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over