1-67320391-G-A

Position:

chr1-67320391-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001374259.2(IL12RB2):c.23G>A(p.Cys8Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,844 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

IL12RB2
NM_001374259.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.618

Variant links:

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]

IL12RB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05378133).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB2	NM_001374259.2 linkuse as main transcript	c.23G>A	p.Cys8Tyr	missense_variant	3/17	ENST00000674203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB2	ENST00000674203.2 linkuse as main transcript	c.23G>A	p.Cys8Tyr	missense_variant	3/17		NM_001374259.2	P1	Q99665-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251254

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461630

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

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

AF:

0.0000920

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 8 of the IL12RB2 protein (p.Cys8Tyr). This variant is present in population databases (rs770452160, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with IL12RB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1349152). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The tyrosine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.47

CADD

Benign

3.6

DANN

Benign

0.30

DEOGEN2

Benign

0.18

T;.;.;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.69

.;T;T;T;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.054

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.5

L;L;.;L;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.0

D;D;D;D;.

REVEL

Benign

0.078

Sift

Benign

0.41

T;T;T;T;.

Sift4G

Benign

1.0

T;T;T;T;.

Polyphen

0.048

B;.;.;B;B

Vest4

0.32

MVP

0.17

MPC

0.23

ClinPred

0.015

GERP RS

0.79

Varity_R

0.056

gMVP

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over