Genetic Variant IL12RB1:p.Ser74Arg (chr19-18082167-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005535.3(IL12RB1):c.222C>G(p.Ser74Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,610,222 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0029 ( 13 hom. )

Consequence

IL12RB1
NM_005535.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.531

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

IL12RB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0109061).

BP6

Variant 19-18082167-G-C is Benign according to our data. Variant chr19-18082167-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 425167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00196 (299/152228) while in subpopulation NFE AF = 0.0031 (211/68018). AF 95% confidence interval is 0.00276. There are 0 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005535.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL12RB1	NM_005535.3	MANE Select	c.222C>G	p.Ser74Arg	missense	Exon 3 of 17	NP_005526.1
IL12RB1	NM_001290024.2		c.342C>G	p.Ser114Arg	missense	Exon 4 of 18	NP_001276953.1
IL12RB1	NM_001440424.1		c.222C>G	p.Ser74Arg	missense	Exon 3 of 17	NP_001427353.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.222C>G	p.Ser74Arg	missense	Exon 3 of 17	ENSP00000472165.2
IL12RB1	ENST00000600835.6	TSL:1	c.222C>G	p.Ser74Arg	missense	Exon 4 of 18	ENSP00000470788.1
IL12RB1	ENST00000322153.11	TSL:1	c.222C>G	p.Ser74Arg	missense	Exon 3 of 10	ENSP00000314425.5

Frequencies

GnomAD3 genomes

AF:

0.00197

AC:

299

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00405

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00310

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00206

AC:

516

AN:

250694

AF XY:

0.00218

show subpopulations

Gnomad AFR exome

AF:

0.000494

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00305

Gnomad NFE exome

AF:

0.00300

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.00288

AC:

4194

AN:

1457994

Hom.:

Cov.:

AF XY:

0.00295

AC XY:

2143

AN XY:

725526

show subpopulations

African (AFR)

AF:

0.000539

AC:

AN:

33400

American (AMR)

AF:

0.000313

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39680

South Asian (SAS)

AF:

0.00305

AC:

263

AN:

86106

European-Finnish (FIN)

AF:

0.00333

AC:

178

AN:

53382

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00324

AC:

3593

AN:

1108612

Other (OTH)

AF:

0.00209

AC:

126

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

190

381

571

762

952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

280

420

560

700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00196

AC:

299

AN:

152228

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

132

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000554

AC:

AN:

41552

American (AMR)

AF:

0.000393

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00187

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00405

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00310

AC:

211

AN:

68018

Other (OTH)

AF:

0.00332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00238

Hom.:

Bravo

AF:

0.00147

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00182

AC:

221

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

IL12RB1: BP4, BS2

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.45

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.8

PhyloP100

0.53

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.1

REVEL

Benign

0.18

Sift4G

Uncertain

0.011

Polyphen

0.87

Vest4

0.32

MutPred

0.49

Gain of MoRF binding (P = 0.0779)

MVP

0.85

MPC

0.10

ClinPred

0.032

GERP RS

-1.2

Varity_R

0.12

gMVP

0.67

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over