rs11575926

Variant names:

• chr19-18077598-C-T
• rs11575926
• NM_005535.3:c.467G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005535.3(IL12RB1):​c.467G>A​(p.Arg156His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,597,014 control chromosomes in the GnomAD database, including 22,380 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (1420 hom., cov: 31)
  • Exomes 𝑓: 0.16 (20960 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.41
• Publications: 35 publications found

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]

IL12RB1 Gene-Disease associations (from GenCC):

• Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002072394).
• BP6: Variant 19-18077598-C-T is Benign according to our data. Variant chr19-18077598-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005535.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	NM_005535.3	MANE Select	c.467G>A	p.Arg156His	missense	Exon 5 of 17	NP_005526.1	P42701-1
	IL12RB1	NM_001290024.2		c.587G>A	p.Arg196His	missense	Exon 6 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.467G>A	p.Arg156His	missense	Exon 5 of 17	NP_001427353.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.467G>A	p.Arg156His	missense	Exon 5 of 17	ENSP00000472165.2	P42701-1
	IL12RB1	ENST00000600835.6	TSL:1	c.467G>A	p.Arg156His	missense	Exon 6 of 18	ENSP00000470788.1	P42701-1
	IL12RB1	ENST00000322153.11	TSL:1	c.467G>A	p.Arg156His	missense	Exon 5 of 10	ENSP00000314425.5	P42701-3

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18197 AN: 152004 Hom.: 1419 Cov.: 31

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.0919

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0796

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.127 AC: 31791 AN: 250760 AF XY: 0.130

Gnomad AFR exome AF: 0.0283

Gnomad AMR exome AF: 0.0677

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.000761

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.163 AC: 234981 AN: 1444892 Hom.: 20960 Cov.: 27 AF XY: 0.161 AC XY: 115887 AN XY: 719732

African (AFR) AF: 0.0236 AC: 783 AN: 33158

American (AMR) AF: 0.0695 AC: 3103 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 4969 AN: 26032

East Asian (EAS) AF: 0.000530 AC: 21 AN: 39618

South Asian (SAS) AF: 0.0819 AC: 7031 AN: 85896

European-Finnish (FIN) AF: 0.184 AC: 9821 AN: 53378

Middle Eastern (MID) AF: 0.144 AC: 827 AN: 5736

European-Non Finnish (NFE) AF: 0.182 AC: 199374 AN: 1096588

Other (OTH) AF: 0.151 AC: 9052 AN: 59812

GnomAD4 genome AF: 0.120 AC: 18201 AN: 152122 Hom.: 1420 Cov.: 31 AF XY: 0.119 AC XY: 8830 AN XY: 74338

African (AFR) AF: 0.0293 AC: 1216 AN: 41532

American (AMR) AF: 0.0918 AC: 1402 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 660 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5176

South Asian (SAS) AF: 0.0810 AC: 391 AN: 4830

European-Finnish (FIN) AF: 0.198 AC: 2088 AN: 10570

Middle Eastern (MID) AF: 0.113 AC: 33 AN: 292

European-Non Finnish (NFE) AF: 0.178 AC: 12064 AN: 67958

Other (OTH) AF: 0.122 AC: 257 AN: 2114

Alfa AF: 0.147 Hom.: 1166

Bravo AF: 0.108

TwinsUK AF: 0.179 AC: 665

ALSPAC AF: 0.189 AC: 729

ESP6500AA AF: 0.0359 AC: 158

ESP6500EA AF: 0.174 AC: 1494

ExAC AF: 0.126 AC: 15244

Asia WGS AF: 0.0350 AC: 123 AN: 3478

EpiCase AF: 0.174

EpiControl AF: 0.167

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Immunodeficiency 27A (2)
-	-	2	Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency (2)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.16
DANN	Benign	0.88
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		-1.4
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.13
Sift4G	Benign	0.093	T
Polyphen		0.014	B
Vest4		0.039
MPC		0.11
ClinPred		0.0016	T
GERP RS		-7.8
Varity_R		0.021
gMVP		0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11575926; hg19: chr19-18188408; COSMIC: COSV59097132; COSMIC: COSV59097132;