1-67367960-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001374259.2(IL12RB2):c.1394G>T(p.Gly465Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G465D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IL12RB2 NM_001374259.2 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19142371).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB2	NM_001374259.2	c.1394G>T	p.Gly465Val	missense_variant	11/17	ENST00000674203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB2	ENST00000674203.2	c.1394G>T	p.Gly465Val	missense_variant	11/17		NM_001374259.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251434 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458146 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725694

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	0.23
Dann	Benign	0.91
DEOGEN2	Benign	0.13	T;.;.;.;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.043	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M;M;.;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.2	D;D;D;D;.
REVEL	Benign	0.087
Sift	Uncertain	0.0050	D;D;D;D;.
Sift4G	Uncertain	0.011	D;D;D;D;.
Polyphen		0.33	B;.;.;D;B
Vest4		0.092
MutPred		0.54		Loss of disorder (P = 0.0391);Loss of disorder (P = 0.0391);Loss of disorder (P = 0.0391);Loss of disorder (P = 0.0391);Loss of disorder (P = 0.0391);
MVP		0.61
MPC		0.18
ClinPred		0.57	D
GERP RS		-3.2
Varity_R		0.24
gMVP		0.44

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: COSV52027200;