NM_001374259.2:c.2337C>A

Variant names:

• chr1-67395837-C-A
• rs2229546
• NM_001374259.2:c.2337C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001374259.2(IL12RB2):​c.2337C>A​(p.Pro779Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.657 in 1,609,934 control chromosomes in the GnomAD database, including 352,274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P779P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.61 (29460 hom., cov: 32)
  • Exomes 𝑓: 0.66 (322814 hom.)
• Consequence: IL12RB2 NM_001374259.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.86
• Publications: 35 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-67395837-C-A is Benign according to our data. Variant chr1-67395837-C-A is described in ClinVar as Benign. ClinVar VariationId is 1164694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB2	NM_001374259.2	c.2337C>A	p.Pro779Pro	synonymous_variant	Exon 17 of 17	ENST00000674203.2	NP_001361188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12RB2	ENST00000674203.2	c.2337C>A	p.Pro779Pro	synonymous_variant	Exon 17 of 17		NM_001374259.2	ENSP00000501329.1

Frequencies

GnomAD3 genomes AF: 0.614 AC: 93381 AN: 151976 Hom.: 29456 Cov.: 32

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.628

Gnomad AMR AF: 0.588

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.751

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.676

Gnomad OTH AF: 0.594

GnomAD2 exomes AF: 0.629 AC: 157582 AN: 250566 AF XY: 0.637

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.570

Gnomad ASJ exome AF: 0.668

Gnomad EAS exome AF: 0.367

Gnomad FIN exome AF: 0.748

Gnomad NFE exome AF: 0.674

Gnomad OTH exome AF: 0.641

GnomAD4 exome AF: 0.662 AC: 964858 AN: 1457840 Hom.: 322814 Cov.: 40 AF XY: 0.663 AC XY: 480592 AN XY: 724676

African (AFR) AF: 0.502 AC: 16725 AN: 33284

American (AMR) AF: 0.566 AC: 25156 AN: 44468

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 17369 AN: 26046

East Asian (EAS) AF: 0.382 AC: 15137 AN: 39608

South Asian (SAS) AF: 0.659 AC: 56782 AN: 86174

European-Finnish (FIN) AF: 0.741 AC: 39555 AN: 53390

Middle Eastern (MID) AF: 0.664 AC: 3818 AN: 5754

European-Non Finnish (NFE) AF: 0.678 AC: 751591 AN: 1108926

Other (OTH) AF: 0.643 AC: 38725 AN: 60190

GnomAD4 genome AF: 0.614 AC: 93423 AN: 152094 Hom.: 29460 Cov.: 32 AF XY: 0.617 AC XY: 45861 AN XY: 74326

African (AFR) AF: 0.510 AC: 21124 AN: 41460

American (AMR) AF: 0.588 AC: 8976 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 2327 AN: 3472

East Asian (EAS) AF: 0.381 AC: 1968 AN: 5160

South Asian (SAS) AF: 0.641 AC: 3093 AN: 4822

European-Finnish (FIN) AF: 0.751 AC: 7951 AN: 10588

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.676 AC: 45994 AN: 68000

Other (OTH) AF: 0.590 AC: 1246 AN: 2112

Alfa AF: 0.640 Hom.: 44474

Bravo AF: 0.592

Asia WGS AF: 0.488 AC: 1697 AN: 3478

EpiCase AF: 0.673

EpiControl AF: 0.666

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

- -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 78% of patients studied by a panel of primary immunodeficiencies. Number of patients: 75. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.053
DANN	Benign	0.36
PhyloP100		-2.9
Mutation Taster		=100/0	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: rs2229546; hg19: chr1-67861520; COSMIC: COSV52025994; COSMIC: COSV52025994;