rs11575925

chr19-18082167-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_005535.3(IL12RB1):c.222C>G(p.Ser74Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,610,222 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0029 (13 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.531

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0109061).
• BP6: Variant 19-18082167-G-C is Benign according to our data. Variant chr19-18082167-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 425167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18082167-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00196 (299/152228) while in subpopulation NFE AF= 0.0031 (211/68018). AF 95% confidence interval is 0.00276. There are 0 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB1	NM_005535.3	c.222C>G	p.Ser74Arg	missense_variant	3/17	ENST00000593993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB1	ENST00000593993.7	c.222C>G	p.Ser74Arg	missense_variant	3/17	1	NM_005535.3	P1

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 299 AN: 152110 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00206 AC: 516 AN: 250694 Hom.: 1 AF XY: 0.00218 AC XY: 295 AN XY: 135548

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00291

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.00300

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.00288 AC: 4194 AN: 1457994 Hom.: 13 Cov.: 30 AF XY: 0.00295 AC XY: 2143 AN XY: 725526

Gnomad4 AFR exome AF: 0.000539

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00305

Gnomad4 FIN exome AF: 0.00333

Gnomad4 NFE exome AF: 0.00324

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152228 Hom.: 0 Cov.: 31 AF XY: 0.00177 AC XY: 132 AN XY: 74444

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.00310

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00238 Hom.: 0

Bravo AF: 0.00147

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00182 AC: 221

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: 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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Likely 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.34	N
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.8	L;L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
Sift4G	Uncertain	0.011	D;D;D;.
Polyphen		0.87	P;P;B;.
Vest4		0.32
MutPred		0.49		Gain of MoRF binding (P = 0.0779);Gain of MoRF binding (P = 0.0779);Gain of MoRF binding (P = 0.0779);.;
MVP		0.85
MPC		0.10
ClinPred		0.032	T
GERP RS		-1.2
Varity_R		0.12
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs11575925; hg19: chr19-18192977; COSMIC: COSV105227065; COSMIC: COSV105227065;