1-67320372-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001374259.2(IL12RB2):c.4G>A(p.Ala2Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IL12RB2 NM_001374259.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.56

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28891516).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB2	NM_001374259.2	c.4G>A	p.Ala2Thr	missense_variant	3/17	ENST00000674203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB2	ENST00000674203.2	c.4G>A	p.Ala2Thr	missense_variant	3/17		NM_001374259.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461606 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 17, 2023

An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with IL12RB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2 of the IL12RB2 protein (p.Ala2Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.2	M;M;.;M;M
MutationTaster	Benign	0.58	D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N;N;N;N;.
REVEL	Benign	0.11
Sift	Uncertain	0.011	D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		1.0	D;.;.;D;D
Vest4		0.38
MutPred		0.21		Gain of glycosylation at A2 (P = 0.0067);Gain of glycosylation at A2 (P = 0.0067);Gain of glycosylation at A2 (P = 0.0067);Gain of glycosylation at A2 (P = 0.0067);Gain of glycosylation at A2 (P = 0.0067);
MVP		0.82
MPC		0.48
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.11
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-67786055;