rs393548

Positions:

chr19-18086934-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1

The ENST00000600835.6(IL12RB1):c.-109-2A>T variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,547,552 control chromosomes in the GnomAD database, including 34,726 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3496 hom., cov: 31)

Exomes 𝑓: 0.21 ( 31230 hom. )

Consequence

IL12RB1
ENST00000600835.6 splice_acceptor

Scores

Splicing: ADA: 0.00006553

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.34

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 -14 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08647562 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.7, offset of 18, new splice context is: tgtcttttctccttgctcAGctt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BP6

Variant 19-18086934-T-A is Benign according to our data. Variant chr19-18086934-T-A is described in ClinVar as [Benign]. Clinvar id is 402972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 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.-111A>T		5_prime_UTR_variant	1/17	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.-111A>T		5_prime_UTR_variant	1/17	1	NM_005535.3	ENSP00000472165	P1	P42701-1

Frequencies

GnomAD3 genomes

AF:

0.212

AC:

32143

AN:

151432

Hom.:

3487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.247

Gnomad AMI

AF:

0.138

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.200

Gnomad EAS

AF:

0.154

Gnomad SAS

AF:

0.190

Gnomad FIN

AF:

0.229

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.210

Gnomad OTH

AF:

0.207

GnomAD3 exomes

AF:

0.193

AC:

29266

AN:

151862

Hom.:

2923

AF XY:

0.195

AC XY:

15839

AN XY:

81364

show subpopulations

Gnomad AFR exome

AF:

0.248

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.209

Gnomad EAS exome

AF:

0.134

Gnomad SAS exome

AF:

0.194

Gnomad FIN exome

AF:

0.221

Gnomad NFE exome

AF:

0.211

Gnomad OTH exome

AF:

0.178

GnomAD4 exome

AF:

0.209

AC:

291921

AN:

1396002

Hom.:

31230

Cov.:

AF XY:

0.209

AC XY:

143993

AN XY:

689156

show subpopulations

Gnomad4 AFR exome

AF:

0.247

Gnomad4 AMR exome

AF:

0.136

Gnomad4 ASJ exome

AF:

0.203

Gnomad4 EAS exome

AF:

0.193

Gnomad4 SAS exome

AF:

0.192

Gnomad4 FIN exome

AF:

0.217

Gnomad4 NFE exome

AF:

0.212

Gnomad4 OTH exome

AF:

0.204

GnomAD4 genome

AF:

0.212

AC:

32195

AN:

151550

Hom.:

3496

Cov.:

AF XY:

0.212

AC XY:

15731

AN XY:

74048

show subpopulations

Gnomad4 AFR

AF:

0.248

Gnomad4 AMR

AF:

0.152

Gnomad4 ASJ

AF:

0.200

Gnomad4 EAS

AF:

0.154

Gnomad4 SAS

AF:

0.191

Gnomad4 FIN

AF:

0.229

Gnomad4 NFE

AF:

0.210

Gnomad4 OTH

AF:

0.209

Alfa

AF:

0.215

Hom.:

680

Bravo

AF:

0.203

Asia WGS

AF:

0.195

AC:

681

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 32% of patients studied by a panel of primary immunodeficiencies. Number of patients: 28. Only high quality variants are reported. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.5

DANN

Benign

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000066

dbscSNV1_RF

Benign

0.0060

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