rs146978336

Positions:

• chr19-18083454-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005535.3(IL12RB1):​c.102G>A​(p.Pro34=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00929 in 1,613,896 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (82 hom.)
• Consequence: IL12RB1 NM_005535.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.97

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-18083454-C-T is Benign according to our data. Variant chr19-18083454-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00627 (954/152240) while in subpopulation NFE AF= 0.00976 (664/68008). AF 95% confidence interval is 0.00915. There are 7 homozygotes in gnomad4. There are 461 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB1	NM_005535.3	c.102G>A	p.Pro34=	synonymous_variant	2/17	ENST00000593993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB1	ENST00000593993.7	c.102G>A	p.Pro34=	synonymous_variant	2/17	1	NM_005535.3	P1

Frequencies

GnomAD3 genomes AF: 0.00628 AC: 955 AN: 152122 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00932

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00976

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00704 AC: 1684 AN: 239204 Hom.: 10 AF XY: 0.00689 AC XY: 890 AN XY: 129204

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.00343

Gnomad ASJ exome AF: 0.00512

Gnomad EAS exome AF: 0.000173

Gnomad SAS exome AF: 0.00256

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00706

GnomAD4 exome AF: 0.00960 AC: 14038 AN: 1461656 Hom.: 82 Cov.: 31 AF XY: 0.00939 AC XY: 6831 AN XY: 727126

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00411

Gnomad4 ASJ exome AF: 0.00501

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00255

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.00780

GnomAD4 genome AF: 0.00627 AC: 954 AN: 152240 Hom.: 7 Cov.: 32 AF XY: 0.00619 AC XY: 461 AN XY: 74462

Gnomad4 AFR AF: 0.00222

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00932

Gnomad4 NFE AF: 0.00976

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00716 Hom.: 1

Bravo AF: 0.00588

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

IL12RB1: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.6
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs146978336; hg19: chr19-18194264;