rs17129792

Positions:

• chr1-67326816-G-A
• chr1-67326816-G-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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:2
• Conservation: PhyloP100: -0.214

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

Verdict is Benign. Variant got -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 id is 774581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-67326816-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB2	NM_001374259.2	c.446G>A	p.Arg149Gln	missense_variant	5/17	ENST00000674203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB2	ENST00000674203.2	c.446G>A	p.Arg149Gln	missense_variant	5/17		NM_001374259.2	P1

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

GnomAD3 exomes AF: 0.00328 AC: 824 AN: 251366 Hom.: 6 AF XY: 0.00286 AC XY: 388 AN XY: 135866

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 SAS exome AF: 0.000915

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

Gnomad4 AFR exome AF: 0.0241

Gnomad4 AMR exome AF: 0.00481

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000974

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00149

Gnomad4 OTH exome AF: 0.00467

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

Gnomad4 AFR AF: 0.0227

Gnomad4 AMR AF: 0.00759

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00325 Hom.: 3

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

IL12RB2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2019

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 v4.3

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;.;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.022	N
MetaRNN	Benign	0.0039	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L;L;.;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-1.8	N;N;N;N;.
REVEL	Benign	0.11
Sift	Benign	0.12	T;T;T;T;.
Sift4G	Uncertain	0.019	D;D;D;D;.
Polyphen		0.0050	B;.;.;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs17129792; hg19: chr1-67792499; COSMIC: COSV52020527;