19-18072285-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.848G>A(p.Arg283Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00862 in 1,613,976 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R283R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (79 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.76

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 (MetaRNN=0.007248014).
• BP6: Variant 19-18072285-C-T is Benign according to our data. Variant chr19-18072285-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18072285-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.006 (913/152230) while in subpopulation NFE AF= 0.00929 (632/68016). AF 95% confidence interval is 0.00869. There are 0 homozygotes in gnomad4. There are 443 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB1	NM_005535.3	c.848G>A	p.Arg283Gln	missense_variant	9/17	ENST00000593993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB1	ENST00000593993.7	c.848G>A	p.Arg283Gln	missense_variant	9/17	1	NM_005535.3	P1
IL12RB1	ENST00000600835.6	c.848G>A	p.Arg283Gln	missense_variant	10/18	1		P1
IL12RB1	ENST00000322153.11	c.848G>A	p.Arg283Gln	missense_variant	9/10	1

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 912 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00374

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00929

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00611 AC: 1534 AN: 251024 Hom.: 7 AF XY: 0.00602 AC XY: 817 AN XY: 135736

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.00857

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00889 AC: 12992 AN: 1461746 Hom.: 79 Cov.: 32 AF XY: 0.00879 AC XY: 6391 AN XY: 727180

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00347

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00218

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00669

GnomAD4 genome AF: 0.00600 AC: 913 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.00595 AC XY: 443 AN XY: 74416

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0122

Gnomad4 NFE AF: 0.00929

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00805 Hom.: 12

Bravo AF: 0.00530

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00552 AC: 670

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00747

EpiControl AF: 0.00771

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	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

IL12RB1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.054
Dann	Benign	0.64
DEOGEN2	Benign	0.16	T;T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0042	N
MetaRNN	Benign	0.0072	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.019	B;B;B
Vest4		0.042
MVP		0.23
MPC		0.097
ClinPred		0.00073	T
GERP RS		-8.7
Varity_R		0.013
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117511121; hg19: chr19-18183095; COSMIC: COSV59099217;