19-18076318-C-T

Position:

chr19-18076318-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_005535.3(IL12RB1):c.559G>A(p.Gly187Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,422,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

IL12RB1
NM_005535.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.299

Variant links:

Genes affected

IL12RB1 (HGNC:5971): (interleukin 12 receptor subunit beta 1) The protein encoded by this gene is a type I transmembrane protein that belongs to the hemopoietin receptor superfamily. This protein binds to interleukine 12 (IL12) with a low affinity, and is thought to be a part of IL12 receptor complex. This protein forms a disulfide-linked oligomer, which is required for its IL12 binding activity. The coexpression of this and IL12RB2 proteins was shown to lead to the formation of high-affinity IL12 binding sites and reconstitution of IL12 dependent signaling. Mutations in this gene impair the development of interleukin-17-producing T lymphocytes and result in increased susceptibility to mycobacterial and Salmonella infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

IL12RB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a domain Fibronectin type-III 2 (size 92) in uniprot entity I12R1_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_005535.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3303283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL12RB1	NM_005535.3 linkuse as main transcript	c.559G>A	p.Gly187Arg	missense_variant	6/17	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7 linkuse as main transcript	c.559G>A	p.Gly187Arg	missense_variant	6/17	1	NM_005535.3	ENSP00000472165	P1	P42701-1
IL12RB1	ENST00000600835.6 linkuse as main transcript	c.559G>A	p.Gly187Arg	missense_variant	7/18	1		ENSP00000470788	P1	P42701-1
IL12RB1	ENST00000322153.11 linkuse as main transcript	c.559G>A	p.Gly187Arg	missense_variant	6/10	1		ENSP00000314425		P42701-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

251192

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1270680

Hom.:

Cov.:

AF XY:

0.0000187

AC XY:

AN XY:

641980

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00000747

Gnomad4 OTH exome

AF:

0.0000185

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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

Bravo

AF:

0.0000264

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.559G>A (p.G187R) alteration is located in exon 6 (coding exon 6) of the IL12RB1 gene. This alteration results from a G to A substitution at nucleotide position 559, causing the glycine (G) at amino acid position 187 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2022

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 187 of the IL12RB1 protein (p.Gly187Arg). This variant is present in population databases (rs564884307, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with IL12RB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 639105). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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

0.16

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.32

T;T;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.74

.;T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Uncertain

-0.022

MutationAssessor

Benign

1.5

L;L;L

MutationTaster

Benign

0.94

N;N

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.7

.;.;D

REVEL

Uncertain

0.35

Sift4G

Uncertain

0.010

D;D;D

Polyphen

0.65

P;P;D

Vest4

0.44

MutPred

0.51

Loss of catalytic residue at G187 (P = 0.0679);Loss of catalytic residue at G187 (P = 0.0679);Loss of catalytic residue at G187 (P = 0.0679);

MVP

0.94

MPC

0.18

ClinPred

0.15

GERP RS

1.5

Varity_R

0.083

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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