Genetic Variant IL12RB1:p.Ala91Thr (chr19-18080970-C-T) – 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.271G>A(p.Ala91Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000847 in 1,613,386 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A91A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00079 ( 30 hom. )

Consequence

IL12RB1
NM_005535.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.714

Publications

6 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=0.004359752).

BP6

Variant 19-18080970-C-T is Benign according to our data. Variant chr19-18080970-C-T is described in ClinVar as Benign. ClinVar VariationId is 328602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00137 (209/152184) while in subpopulation EAS AF = 0.0375 (194/5172). AF 95% confidence interval is 0.0332. There are 2 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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.271G>A	p.Ala91Thr	missense	Exon 4 of 17	NP_005526.1
IL12RB1	NM_001290024.2		c.391G>A	p.Ala131Thr	missense	Exon 5 of 18	NP_001276953.1
IL12RB1	NM_001440424.1		c.271G>A	p.Ala91Thr	missense	Exon 4 of 17	NP_001427353.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.271G>A	p.Ala91Thr	missense	Exon 4 of 17	ENSP00000472165.2
IL12RB1	ENST00000600835.6	TSL:1	c.271G>A	p.Ala91Thr	missense	Exon 5 of 18	ENSP00000470788.1
IL12RB1	ENST00000322153.11	TSL:1	c.271G>A	p.Ala91Thr	missense	Exon 4 of 10	ENSP00000314425.5

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

212

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0380

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.00349

AC:

876

AN:

250756

AF XY:

0.00331

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0466

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000792

AC:

1158

AN:

1461202

Hom.:

Cov.:

AF XY:

0.000764

AC XY:

555

AN XY:

726876

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0268

AC:

1062

AN:

39698

South Asian (SAS)

AF:

0.000104

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53112

Middle Eastern (MID)

AF:

0.000355

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

1111852

Other (OTH)

AF:

0.000812

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

128

191

255

319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00137

AC:

209

AN:

152184

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

130

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41534

American (AMR)

AF:

0.000327

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0375

AC:

194

AN:

5172

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68010

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00119

Hom.:

Bravo

AF:

0.00172

ExAC

AF:

0.00306

AC:

371

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: 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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

IL12RB1-related disorder

Benign:1

Jun 25, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.59

CADD

Benign

1.3

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.11

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0070

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0044

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.93

PhyloP100

-0.71

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.2

REVEL

Benign

0.076

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.068

MVP

0.58

MPC

0.082

ClinPred

0.0023

GERP RS

-0.16

Varity_R

0.021

gMVP

0.25

Mutation Taster

=100/0

polymorphism

(source)

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

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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