19-18075808-T-C

Position:

chr19-18075808-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_005535.3(IL12RB1):c.641A>G(p.Gln214Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,611,352 control chromosomes in the GnomAD database, including 75,833 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5580 hom., cov: 32)

Exomes 𝑓: 0.31 ( 70253 hom. )

Consequence

IL12RB1
NM_005535.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.194

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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005535.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0024283528).

BP6

Variant 19-18075808-T-C is Benign according to our data. Variant chr19-18075808-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 328597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18075808-T-C is described in Lovd as [Benign]. Variant chr19-18075808-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB1	NM_005535.3 linkuse as main transcript	c.641A>G	p.Gln214Arg	missense_variant	7/17	ENST00000593993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB1	ENST00000593993.7 linkuse as main transcript	c.641A>G	p.Gln214Arg	missense_variant	7/17	1	NM_005535.3	P1	P42701-1
IL12RB1	ENST00000600835.6 linkuse as main transcript	c.641A>G	p.Gln214Arg	missense_variant	8/18	1		P1	P42701-1
IL12RB1	ENST00000322153.11 linkuse as main transcript	c.641A>G	p.Gln214Arg	missense_variant	7/10	1			P42701-3

Frequencies

GnomAD3 genomes

AF:

0.254

AC:

38637

AN:

151984

Hom.:

5570

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.246

Gnomad AMR

AF:

0.207

Gnomad ASJ

AF:

0.325

Gnomad EAS

AF:

0.371

Gnomad SAS

AF:

0.238

Gnomad FIN

AF:

0.337

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.320

Gnomad OTH

AF:

0.261

GnomAD3 exomes

AF:

0.277

AC:

69637

AN:

251238

Hom.:

10362

AF XY:

0.283

AC XY:

38412

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.121

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.336

Gnomad EAS exome

AF:

0.354

Gnomad SAS exome

AF:

0.225

Gnomad FIN exome

AF:

0.326

Gnomad NFE exome

AF:

0.321

Gnomad OTH exome

AF:

0.280

GnomAD4 exome

AF:

0.306

AC:

446325

AN:

1459250

Hom.:

70253

Cov.:

AF XY:

0.305

AC XY:

221603

AN XY:

726102

show subpopulations

Gnomad4 AFR exome

AF:

0.119

Gnomad4 AMR exome

AF:

0.167

Gnomad4 ASJ exome

AF:

0.333

Gnomad4 EAS exome

AF:

0.385

Gnomad4 SAS exome

AF:

0.230

Gnomad4 FIN exome

AF:

0.325

Gnomad4 NFE exome

AF:

0.319

Gnomad4 OTH exome

AF:

0.299

GnomAD4 genome

AF:

0.254

AC:

38675

AN:

152102

Hom.:

5580

Cov.:

AF XY:

0.256

AC XY:

19037

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.124

Gnomad4 AMR

AF:

0.206

Gnomad4 ASJ

AF:

0.325

Gnomad4 EAS

AF:

0.371

Gnomad4 SAS

AF:

0.239

Gnomad4 FIN

AF:

0.337

Gnomad4 NFE

AF:

0.320

Gnomad4 OTH

AF:

0.266

Alfa

AF:

0.312

Hom.:

13145

Bravo

AF:

0.238

TwinsUK

AF:

0.312

AC:

1158

ALSPAC

AF:

0.323

AC:

1244

ESP6500AA

AF:

0.131

AC:

578

ESP6500EA

AF:

0.316

AC:

2715

ExAC

AF:

0.276

AC:

33563

Asia WGS

AF:

0.322

AC:

1121

AN:

3478

EpiCase

AF:

0.321

EpiControl

AF:

0.316

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 31. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, no convincing disease association -

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

Immunodeficiency 27A

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 09, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.021

DANN

Benign

0.11

DEOGEN2

Benign

0.080

T;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.18

.;T;T

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

N;N;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.24

PROVEAN

Benign

1.0

.;.;N

REVEL

Benign

0.15

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.038

MPC

0.090

ClinPred

0.0042

GERP RS

1.7

Varity_R

0.018

gMVP

0.31

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