rs17852635

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005535.3(IL12RB1):c.684C>T(p.Pro228Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,610,226 control chromosomes in the GnomAD database, including 75,834 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5580 hom., cov: 31)

Exomes 𝑓: 0.31 ( 70254 hom. )

Consequence

IL12RB1
NM_005535.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.47

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 19-18075765-G-A is Benign according to our data. Variant chr19-18075765-G-A is described in ClinVar as [Benign]. Clinvar id is 328596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18075765-G-A is described in Lovd as [Benign]. Variant chr19-18075765-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.47 with no splicing effect.

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/exons	MANE	Protein	UniProt
IL12RB1	NM_005535.3 linkuse as main transcript	c.684C>T	p.Pro228Pro	synonymous_variant	7/17	ENST00000593993.7	NP_005526.1	P42701-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IL12RB1	ENST00000593993.7 linkuse as main transcript	c.684C>T	p.Pro228Pro	synonymous_variant	7/17	1	NM_005535.3	ENSP00000472165.2	P42701-1
IL12RB1	ENST00000600835.6 linkuse as main transcript	c.684C>T	p.Pro228Pro	synonymous_variant	8/18	1		ENSP00000470788.1	P42701-1
IL12RB1	ENST00000322153.11 linkuse as main transcript	c.684C>T	p.Pro228Pro	synonymous_variant	7/10	1		ENSP00000314425.5	P42701-3

Frequencies

GnomAD3 genomes

AF:

0.255

AC:

38678

AN:

151868

Hom.:

5570

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.249

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:

0.262

GnomAD3 exomes

AF:

0.277

AC:

69678

AN:

251328

Hom.:

10367

AF XY:

0.283

AC XY:

38438

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.336

Gnomad EAS exome

AF:

0.354

Gnomad SAS exome

AF:

0.226

Gnomad FIN exome

AF:

0.326

Gnomad NFE exome

AF:

0.321

Gnomad OTH exome

AF:

0.280

GnomAD4 exome

AF:

0.306

AC:

445884

AN:

1458240

Hom.:

70254

Cov.:

AF XY:

0.305

AC XY:

221407

AN XY:

725652

show subpopulations

Gnomad4 AFR exome

AF:

0.120

Gnomad4 AMR exome

AF:

0.167

Gnomad4 ASJ exome

AF:

0.333

Gnomad4 EAS exome

AF:

0.385

Gnomad4 SAS exome

AF:

0.231

Gnomad4 FIN exome

AF:

0.325

Gnomad4 NFE exome

AF:

0.319

Gnomad4 OTH exome

AF:

0.299

GnomAD4 genome

AF:

0.255

AC:

38713

AN:

151986

Hom.:

5580

Cov.:

AF XY:

0.256

AC XY:

19047

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.126

Gnomad4 AMR

AF:

0.206

Gnomad4 ASJ

AF:

0.325

Gnomad4 EAS

AF:

0.371

Gnomad4 SAS

AF:

0.239

Gnomad4 FIN

AF:

0.337

Gnomad4 NFE

AF:

0.320

Gnomad4 OTH

AF:

0.266

Alfa

AF:

0.297

Hom.:

8973

Bravo

AF:

0.239

Asia WGS

AF:

0.322

AC:

1120

AN:

3478

EpiCase

AF:

0.321

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -

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 -
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

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.12

DANN

Benign

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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