NM_001374259.2:c.446G>A

Variant names:

• chr1-67326816-G-A
• rs17129792
• NM_001374259.2:c.446G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374259.2(IL12RB2):​c.446G>A​(p.Arg149Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,613,810 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (28 hom.)
• Consequence: IL12RB2 NM_001374259.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.214
• Publications: 10 publications found

Genes affected

IL12RB2 (HGNC:5972): (interleukin 12 receptor subunit beta 2) The protein encoded by this gene is a type I transmembrane protein identified as a subunit of the interleukin 12 receptor complex. The coexpression of this and IL12RB1 proteins was shown to lead to the formation of high-affinity IL12 binding sites and reconstitution of IL12 dependent signaling. The expression of this gene is up-regulated by interferon gamma in Th1 cells, and plays a role in Th1 cell differentiation. The up-regulation of this gene is found to be associated with a number of infectious diseases, such as Crohn's disease and leprosy, which is thought to contribute to the inflammatory response and host defense. Several transcript variants encoding different isoforms and non-protein coding transcripts have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038602352).
• BP6: Variant 1-67326816-G-A is Benign according to our data. Variant chr1-67326816-G-A is described in ClinVar as Benign. ClinVar VariationId is 774581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00819 (1247/152240) while in subpopulation AFR AF = 0.0227 (942/41566). AF 95% confidence interval is 0.0215. There are 13 homozygotes in GnomAd4. There are 581 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374259.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB2	NM_001374259.2	MANE Select	c.446G>A	p.Arg149Gln	missense	Exon 5 of 17	NP_001361188.1
	IL12RB2	NM_001559.3		c.446G>A	p.Arg149Gln	missense	Exon 4 of 16	NP_001550.1
	IL12RB2	NM_001258215.1		c.446G>A	p.Arg149Gln	missense	Exon 4 of 14	NP_001245144.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB2	ENST00000674203.2	MANE Select	c.446G>A	p.Arg149Gln	missense	Exon 5 of 17	ENSP00000501329.1
	IL12RB2	ENST00000262345.5	TSL:1	c.446G>A	p.Arg149Gln	missense	Exon 4 of 16	ENSP00000262345.1
	IL12RB2	ENST00000544434.5	TSL:1	c.446G>A	p.Arg149Gln	missense	Exon 4 of 14	ENSP00000442443.1

Frequencies

GnomAD3 genomes AF: 0.00816 AC: 1241 AN: 152124 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00760

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00328 AC: 824 AN: 251366 AF XY: 0.00286

Gnomad AFR exome AF: 0.0220

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00217 AC: 3175 AN: 1461570 Hom.: 28 Cov.: 31 AF XY: 0.00210 AC XY: 1527 AN XY: 727096

African (AFR) AF: 0.0241 AC: 807 AN: 33464

American (AMR) AF: 0.00481 AC: 215 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000974 AC: 84 AN: 86234

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53388

Middle Eastern (MID) AF: 0.0151 AC: 87 AN: 5768

European-Non Finnish (NFE) AF: 0.00149 AC: 1657 AN: 1111818

Other (OTH) AF: 0.00467 AC: 282 AN: 60370

GnomAD4 genome AF: 0.00819 AC: 1247 AN: 152240 Hom.: 13 Cov.: 32 AF XY: 0.00781 AC XY: 581 AN XY: 74430

African (AFR) AF: 0.0227 AC: 942 AN: 41566

American (AMR) AF: 0.00759 AC: 116 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.00190 AC: 129 AN: 67994

Other (OTH) AF: 0.0156 AC: 33 AN: 2116

Alfa AF: 0.00417 Hom.: 8

Bravo AF: 0.00948

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0229 AC: 101

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00352 AC: 427

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00356

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

IL12RB2-related disorder Benign:1

Feb 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.6
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.21
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.11
Sift	Benign	0.12	T
Sift4G	Uncertain	0.019	D
Polyphen		0.0050	B
Vest4		0.12
MVP		0.31
MPC		0.18
ClinPred		0.016	T
GERP RS		-2.2
Varity_R		0.047
gMVP		0.29
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17129792; hg19: chr1-67792499; COSMIC: COSV52020527;