rs140254802

Positions:

• chr19-18069563-G-A
• chr19-18069563-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005535.3(IL12RB1):​c.1172C>T​(p.Pro391Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,610,118 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4 O:1
• Conservation: PhyloP100: -6.21

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008534402).
• BP6: Variant 19-18069563-G-A is Benign according to our data. Variant chr19-18069563-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474975.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, not_provided=1}. Variant chr19-18069563-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00119 (181/152356) while in subpopulation NFE AF= 0.00194 (132/68034). AF 95% confidence interval is 0.00167. There are 1 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.1172C>T	p.Pro391Leu	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	c.1172C>T	p.Pro391Leu	missense_variant	10/17	1	NM_005535.3	ENSP00000472165.2
IL12RB1	ENST00000600835.6	c.1172C>T	p.Pro391Leu	missense_variant	11/18	1		ENSP00000470788.1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152238 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00101 AC: 246 AN: 244446 Hom.: 0 AF XY: 0.00102 AC XY: 136 AN XY: 133076

Gnomad AFR exome AF: 0.000520

Gnomad AMR exome AF: 0.000988

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00178

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.00188 AC: 2747 AN: 1457762 Hom.: 3 Cov.: 31 AF XY: 0.00183 AC XY: 1325 AN XY: 725352

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000985

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000802

Gnomad4 NFE exome AF: 0.00233

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152356 Hom.: 1 Cov.: 32 AF XY: 0.000980 AC XY: 73 AN XY: 74498

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00179 Hom.: 1

Bravo AF: 0.00138

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000746 AC: 3

ESP6500EA AF: 0.00157 AC: 13

ExAC AF: 0.000918 AC: 111

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2 Other:1

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Likely benign and reported on 09-24-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

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

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

IL12RB1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.0040
DANN	Benign	0.68
DEOGEN2	Benign	0.078	T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.65	.;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.0085	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.67	N;N
PrimateAI	Benign	0.23	T
Sift4G	Uncertain	0.054	T;T
Polyphen		0.014	B;B
Vest4		0.091
MVP		0.53
MPC		0.086
ClinPred		0.0086	T
GERP RS		-6.2
Varity_R		0.025
gMVP		0.29

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

Other links and lift over

dbSNP: rs140254802; hg19: chr19-18180373;