rs145590794

Positions:

chr19-18060064-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005535.3(IL12RB1):c.1813G>T(p.Val605Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,603,074 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 4 hom. )

Consequence

IL12RB1
NM_005535.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.436

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073914826).

BP6

Variant 19-18060064-C-A is Benign according to our data. Variant chr19-18060064-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 541821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18060064-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00205 (313/152346) while in subpopulation NFE AF= 0.00273 (186/68032). AF 95% confidence interval is 0.00241. There are 1 homozygotes in gnomad4. There are 165 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL12RB1	NM_005535.3 linkuse as main transcript	c.1813G>T	p.Val605Leu	missense_variant	16/17	ENST00000593993.7	NP_005526.1	P42701-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7 linkuse as main transcript	c.1813G>T	p.Val605Leu	missense_variant	16/17	1	NM_005535.3	ENSP00000472165.2		P42701-1
IL12RB1	ENST00000600835.6 linkuse as main transcript	c.1813G>T	p.Val605Leu	missense_variant	17/18	1		ENSP00000470788.1		P42701-1

Frequencies

GnomAD3 genomes

AF:

0.00206

AC:

313

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00838

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00273

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00179

AC:

435

AN:

242972

Hom.:

AF XY:

0.00185

AC XY:

244

AN XY:

131708

show subpopulations

Gnomad AFR exome

AF:

0.000204

Gnomad AMR exome

AF:

0.000767

Gnomad ASJ exome

AF:

0.000308

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000270

Gnomad FIN exome

AF:

0.00559

Gnomad NFE exome

AF:

0.00246

Gnomad OTH exome

AF:

0.00101

GnomAD4 exome

AF:

0.00238

AC:

3457

AN:

1450728

Hom.:

Cov.:

AF XY:

0.00241

AC XY:

1737

AN XY:

721982

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000904

Gnomad4 ASJ exome

AF:

0.000541

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000422

Gnomad4 FIN exome

AF:

0.00599

Gnomad4 NFE exome

AF:

0.00266

Gnomad4 OTH exome

AF:

0.00173

GnomAD4 genome

AF:

0.00205

AC:

313

AN:

152346

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

165

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00838

Gnomad4 NFE

AF:

0.00273

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00254

Hom.:

Bravo

AF:

0.00144

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000499

AC:

ESP6500EA

AF:

0.00228

AC:

ExAC

AF:

0.00174

AC:

210

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

IL12RB1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.20

T;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.69

.;T

M_CAP

Benign

0.082

MetaRNN

Benign

0.0074

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.29

Sift4G

Benign

0.28

T;T

Polyphen

0.12

B;B

Vest4

0.069

MutPred

0.16

Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);

MVP

0.80

MPC

0.094

ClinPred

0.015

GERP RS

2.5

Varity_R

0.052

gMVP

0.14

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