rs2307153

chr1-67367960-G-Achr1-67367960-G-T

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.1394G>A(p.Gly465Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,610,054 control chromosomes in the GnomAD database, including 342 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 0.015 (21 hom., cov: 32)
  • Exomes 𝑓: 0.019 (321 hom.)
• Consequence: IL12RB2 NM_001374259.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.840

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=0.003908336).
• BP6: Variant 1-67367960-G-A is Benign according to our data. Variant chr1-67367960-G-A is described in ClinVar as [Benign]. Clinvar id is 1166571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-67367960-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0146 (2229/152266) while in subpopulation NFE AF= 0.0226 (1539/68010). AF 95% confidence interval is 0.0217. There are 21 homozygotes in gnomad4. There are 1067 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB2	NM_001374259.2	c.1394G>A	p.Gly465Asp	missense_variant	11/17	ENST00000674203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB2	ENST00000674203.2	c.1394G>A	p.Gly465Asp	missense_variant	11/17		NM_001374259.2	P1

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2229 AN: 152148 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0226

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0139 AC: 3498 AN: 251434 Hom.: 40 AF XY: 0.0140 AC XY: 1902 AN XY: 135898

Gnomad AFR exome AF: 0.00326

Gnomad AMR exome AF: 0.00971

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.0220

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0195 AC: 28393 AN: 1457788 Hom.: 321 Cov.: 29 AF XY: 0.0190 AC XY: 13804 AN XY: 725540

Gnomad4 AFR exome AF: 0.00353

Gnomad4 AMR exome AF: 0.0108

Gnomad4 ASJ exome AF: 0.00234

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000592

Gnomad4 FIN exome AF: 0.0222

Gnomad4 NFE exome AF: 0.0229

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0146 AC: 2229 AN: 152266 Hom.: 21 Cov.: 32 AF XY: 0.0143 AC XY: 1067 AN XY: 74446

Gnomad4 AFR AF: 0.00407

Gnomad4 AMR AF: 0.0159

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0225

Gnomad4 NFE AF: 0.0226

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0195 Hom.: 67

Bravo AF: 0.0137

TwinsUK AF: 0.0256 AC: 95

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0190 AC: 163

ExAC AF: 0.0141 AC: 1711

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0206

EpiControl AF: 0.0198

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 31, 2024

- -

IL12RB2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 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	0.069
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.14
Dann	Benign	0.27
DEOGEN2	Benign	0.069	T;.;.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.030	N
MetaRNN	Benign	0.0039	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.9	M;M;.;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.5	N;N;N;N;.
REVEL	Benign	0.038
Sift	Benign	0.13	T;T;T;T;.
Sift4G	Uncertain	0.0070	D;D;D;D;.
Polyphen		0.0020	B;.;.;B;B
Vest4		0.018
MPC		0.18
ClinPred		0.012	T
GERP RS		-3.2
Varity_R		0.096
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs2307153; hg19: chr1-67833643; COSMIC: COSV99255249;