rs393548

chr19-18086934-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

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:3
• Conservation: PhyloP100: -1.34

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PVS1: Splicing variant, 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	UniProt
IL12RB1	NM_005535.3	c.-111A>T		5_prime_UTR_variant	1/17	ENST00000593993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB1	ENST00000593993.7	c.-111A>T		5_prime_UTR_variant	1/17	1	NM_005535.3	P1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32143 AN: 151432 Hom.: 3487 Cov.: 31

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

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.: 32 AF XY: 0.209 AC XY: 143993 AN XY: 689156

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.: 31 AF XY: 0.212 AC XY: 15731 AN XY: 74048

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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. -
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 -

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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

Other links and lift over

dbSNP: rs393548; hg19: chr19-18197744; COSMIC: COSV59096451; COSMIC: COSV59096451;