1-67367960-G-A

Variant names:

• chr1-67367960-G-A
• rs2307153
• NM_001374259.2:c.1394G>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.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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:3
• Conservation: PhyloP100: -0.840
• Publications: 22 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=0.003908336).
• BP6: Variant 1-67367960-G-A is Benign according to our data. Variant chr1-67367960-G-A is described in ClinVar as Benign. ClinVar VariationId is 1166571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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.1394G>A	p.Gly465Asp	missense	Exon 11 of 17	NP_001361188.1
	IL12RB2	NM_001559.3		c.1394G>A	p.Gly465Asp	missense	Exon 10 of 16	NP_001550.1
	IL12RB2	NM_001258215.1		c.1394G>A	p.Gly465Asp	missense	Exon 10 of 14	NP_001245144.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB2	ENST00000674203.2	MANE Select	c.1394G>A	p.Gly465Asp	missense	Exon 11 of 17	ENSP00000501329.1
	IL12RB2	ENST00000262345.5	TSL:1	c.1394G>A	p.Gly465Asp	missense	Exon 10 of 16	ENSP00000262345.1
	IL12RB2	ENST00000544434.5	TSL:1	c.1394G>A	p.Gly465Asp	missense	Exon 10 of 14	ENSP00000442443.1

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

GnomAD2 exomes AF: 0.0139 AC: 3498 AN: 251434 AF XY: 0.0140

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 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

African (AFR) AF: 0.00353 AC: 118 AN: 33416

American (AMR) AF: 0.0108 AC: 484 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00234 AC: 61 AN: 26110

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39680

South Asian (SAS) AF: 0.000592 AC: 51 AN: 86186

European-Finnish (FIN) AF: 0.0222 AC: 1187 AN: 53418

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5754

European-Non Finnish (NFE) AF: 0.0229 AC: 25410 AN: 1108278

Other (OTH) AF: 0.0178 AC: 1070 AN: 60224

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

African (AFR) AF: 0.00407 AC: 169 AN: 41558

American (AMR) AF: 0.0159 AC: 243 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0225 AC: 239 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0226 AC: 1539 AN: 68010

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.0191 Hom.: 125

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IL12RB2-related disorder Benign:1

Mar 06, 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	0.069
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.14
DANN	Benign	0.27
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		-0.84
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.038
Sift	Benign	0.13	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.0020	B
Vest4		0.018
MPC		0.18
ClinPred		0.012	T
GERP RS		-3.2
Varity_R		0.096
gMVP		0.48
Mutation Taster		=98/2	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: rs2307153; hg19: chr1-67833643; COSMIC: COSV99255249;