1-67367844-G-C

Variant names:

• chr1-67367844-G-C
• rs2307145
• NM_001374259.2:c.1278G>C

Variant summary

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

The NM_001374259.2(IL12RB2):​c.1278G>C​(p.Gln426His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0439 in 1,595,256 control chromosomes in the GnomAD database, including 1,780 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Q426Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.054 (271 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1509 hom.)
• Consequence: IL12RB2 NM_001374259.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0580
• Publications: 20 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=0.0032021403).
• BP6: Variant 1-67367844-G-C is Benign according to our data. Variant chr1-67367844-G-C is described in ClinVar as Benign. ClinVar VariationId is 1165356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB2	NM_001374259.2	c.1278G>C	p.Gln426His	missense_variant	Exon 11 of 17	ENST00000674203.2	NP_001361188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12RB2	ENST00000674203.2	c.1278G>C	p.Gln426His	missense_variant	Exon 11 of 17		NM_001374259.2	ENSP00000501329.1

Frequencies

GnomAD3 genomes AF: 0.0539 AC: 8192 AN: 152018 Hom.: 269 Cov.: 32

Gnomad AFR AF: 0.0805

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0522

Gnomad ASJ AF: 0.0879

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0291

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0477

Gnomad OTH AF: 0.0631

GnomAD2 exomes AF: 0.0389 AC: 9773 AN: 251432 AF XY: 0.0378

Gnomad AFR exome AF: 0.0787

Gnomad AMR exome AF: 0.0340

Gnomad ASJ exome AF: 0.0781

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0254

Gnomad NFE exome AF: 0.0464

Gnomad OTH exome AF: 0.0468

GnomAD4 exome AF: 0.0429 AC: 61871 AN: 1443120 Hom.: 1509 Cov.: 27 AF XY: 0.0423 AC XY: 30424 AN XY: 719346

African (AFR) AF: 0.0782 AC: 2587 AN: 33076

American (AMR) AF: 0.0370 AC: 1652 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0832 AC: 2163 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.0147 AC: 1259 AN: 85902

European-Finnish (FIN) AF: 0.0277 AC: 1482 AN: 53408

Middle Eastern (MID) AF: 0.0487 AC: 278 AN: 5712

European-Non Finnish (NFE) AF: 0.0455 AC: 49813 AN: 1094944

Other (OTH) AF: 0.0441 AC: 2637 AN: 59766

GnomAD4 genome AF: 0.0539 AC: 8207 AN: 152136 Hom.: 271 Cov.: 32 AF XY: 0.0520 AC XY: 3871 AN XY: 74392

African (AFR) AF: 0.0806 AC: 3346 AN: 41500

American (AMR) AF: 0.0521 AC: 796 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0879 AC: 305 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0127 AC: 61 AN: 4820

European-Finnish (FIN) AF: 0.0291 AC: 308 AN: 10584

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0477 AC: 3244 AN: 67976

Other (OTH) AF: 0.0624 AC: 132 AN: 2114

Alfa AF: 0.0428 Hom.: 147

Bravo AF: 0.0565

TwinsUK AF: 0.0512 AC: 190

ALSPAC AF: 0.0524 AC: 202

ESP6500AA AF: 0.0785 AC: 346

ESP6500EA AF: 0.0485 AC: 417

ExAC AF: 0.0386 AC: 4685

EpiCase AF: 0.0511

EpiControl AF: 0.0526

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

Mar 02, 2020

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.8
DANN	Benign	0.95
DEOGEN2	Benign	0.064	T;.;.;.;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.0	.;T;T;T;T
MetaRNN	Benign	0.0032	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M;.;M;M
PhyloP100		0.058
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.66	N;N;N;N;.
REVEL	Benign	0.051
Sift	Benign	0.14	T;T;T;T;.
Sift4G	Benign	0.069	T;T;T;T;.
Vest4		0.017
ClinPred		0.015	T
GERP RS		2.0
Varity_R		0.069
gMVP		0.33
Mutation Taster		=94/6	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: rs2307145; hg19: chr1-67833527;