Genetic Variant IL12RB1:c.125-539T>C (chr19-18082803-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is . The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005535.3(IL12RB1):c.125-539T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 152,050 control chromosomes in the GnomAD database, including 40,447 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.73 ( 40447 hom., cov: 32)

Consequence

IL12RB1
NM_005535.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.54

Publications

4 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: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)

IL12RB1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_005535.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.03).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
IL12RB1	NM_005535.3	MANE Select	c.125-539T>C	intron	N/A	NP_005526.1	P42701-1
IL12RB1	NM_001290024.2		c.245-539T>C	intron	N/A	NP_001276953.1
IL12RB1	NM_001440424.1		c.125-539T>C	intron	N/A	NP_001427353.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.125-539T>C	intron	N/A	ENSP00000472165.2	P42701-1
IL12RB1	ENST00000600835.6	TSL:1	c.125-539T>C	intron	N/A	ENSP00000470788.1	P42701-1
IL12RB1	ENST00000322153.11	TSL:1	c.125-539T>C	intron	N/A	ENSP00000314425.5	P42701-3

Frequencies

GnomAD3 genomes

AF:

0.726

AC:

110235

AN:

151932

Hom.:

40422

Cov.:

show subpopulations

Gnomad AFR

AF:

0.637

Gnomad AMI

AF:

0.754

Gnomad AMR

AF:

0.680

Gnomad ASJ

AF:

0.795

Gnomad EAS

AF:

0.938

Gnomad SAS

AF:

0.831

Gnomad FIN

AF:

0.793

Gnomad MID

AF:

0.750

Gnomad NFE

AF:

0.752

Gnomad OTH

AF:

0.719

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.726

AC:

110314

AN:

152050

Hom.:

40447

Cov.:

AF XY:

0.730

AC XY:

54248

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.637

AC:

26387

AN:

41424

American (AMR)

AF:

0.679

AC:

10370

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.795

AC:

2757

AN:

3468

East Asian (EAS)

AF:

0.938

AC:

4861

AN:

5182

South Asian (SAS)

AF:

0.832

AC:

4015

AN:

4828

European-Finnish (FIN)

AF:

0.793

AC:

8392

AN:

10586

Middle Eastern (MID)

AF:

0.748

AC:

220

AN:

294

European-Non Finnish (NFE)

AF:

0.752

AC:

51103

AN:

67984

Other (OTH)

AF:

0.722

AC:

1523

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1515

3030

4545

6060

7575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

842

1684

2526

3368

4210

<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:

0.740

Hom.:

15391

Bravo

AF:

0.708

Asia WGS

AF:

0.870

AC:

3024

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

1.6

(source)

DANN

Benign

0.20

PhyloP100

-1.5

Mutation Taster

=100/0

polymorphism (auto)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over