rs393548

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1

The NM_001290024.2(IL12RB1):c.12-2A>T variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,547,552 control chromosomes in the GnomAD database, including 34,726 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3496 hom., cov: 31)

Exomes 𝑓: 0.21 ( 31230 hom. )

Consequence

IL12RB1
NM_001290024.2 splice_acceptor, intron

Scores

Splicing: ADA: 0.00006553

Clinical Significance

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

Conservation

PhyloP100: -1.34

Publications

28 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, Labcorp Genetics (formerly Invitae)

IL12RB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.082029395 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.7, offset of 18, new splice context is: tgtcttttctccttgctcAGctt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BP6

Variant 19-18086934-T-A is Benign according to our data. Variant chr19-18086934-T-A is described in ClinVar as Benign. ClinVar VariationId is 402972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290024.2. 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.-111A>T	5_prime_UTR	Exon 1 of 17	NP_005526.1	P42701-1
IL12RB1	NM_001440424.1		c.-111A>T	5_prime_UTR	Exon 1 of 17	NP_001427353.1
IL12RB1	NM_001440425.1		c.-111A>T	5_prime_UTR	Exon 1 of 17	NP_001427354.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.-111A>T	5_prime_UTR	Exon 1 of 17	ENSP00000472165.2	P42701-1
IL12RB1	ENST00000600835.6	TSL:1	c.-109-2A>T	splice_acceptor intron	N/A	ENSP00000470788.1	P42701-1
IL12RB1	ENST00000430026.7	TSL:4	c.-111A>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000403103.3	X6RGM1

Frequencies

GnomAD3 genomes

AF:

0.212

AC:

32143

AN:

151432

Hom.:

3487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.247

Gnomad AMI

AF:

0.138

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.200

Gnomad EAS

AF:

0.154

Gnomad SAS

AF:

0.190

Gnomad FIN

AF:

0.229

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.210

Gnomad OTH

AF:

0.207

GnomAD2 exomes

AF:

0.193

AC:

29266

AN:

151862

AF XY:

0.195

show subpopulations

Gnomad AFR exome

AF:

0.248

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.209

Gnomad EAS exome

AF:

0.134

Gnomad FIN exome

AF:

0.221

Gnomad NFE exome

AF:

0.211

Gnomad OTH exome

AF:

0.178

GnomAD4 exome

AF:

0.209

AC:

291921

AN:

1396002

Hom.:

31230

Cov.:

AF XY:

0.209

AC XY:

143993

AN XY:

689156

show subpopulations

African (AFR)

AF:

0.247

AC:

7727

AN:

31248

American (AMR)

AF:

0.136

AC:

4784

AN:

35208

Ashkenazi Jewish (ASJ)

AF:

0.203

AC:

5099

AN:

25070

East Asian (EAS)

AF:

0.193

AC:

6931

AN:

35846

South Asian (SAS)

AF:

0.192

AC:

15243

AN:

79506

European-Finnish (FIN)

AF:

0.217

AC:

10269

AN:

47288

Middle Eastern (MID)

AF:

0.191

AC:

1084

AN:

5682

European-Non Finnish (NFE)

AF:

0.212

AC:

228993

AN:

1078274

Other (OTH)

AF:

0.204

AC:

11791

AN:

57880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

10742

21484

32226

42968

53710

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8060

16120

24180

32240

40300

<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:

0.212

AC:

32195

AN:

151550

Hom.:

3496

Cov.:

AF XY:

0.212

AC XY:

15731

AN XY:

74048

show subpopulations

African (AFR)

AF:

0.248

AC:

10214

AN:

41268

American (AMR)

AF:

0.152

AC:

2322

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

692

AN:

3466

East Asian (EAS)

AF:

0.154

AC:

798

AN:

5168

South Asian (SAS)

AF:

0.191

AC:

921

AN:

4816

European-Finnish (FIN)

AF:

0.229

AC:

2392

AN:

10430

Middle Eastern (MID)

AF:

0.137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.210

AC:

14251

AN:

67858

Other (OTH)

AF:

0.209

AC:

439

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1318

2635

3953

5270

6588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.215

Hom.:

680

Bravo

AF:

0.203

Asia WGS

AF:

0.195

AC:

681

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.5

(source)

DANN

Benign

0.54

PhyloP100

-1.3

PromoterAI

-0.074

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000066

dbscSNV1_RF

Benign

0.0060

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

Computational scores

Splicing

Publications

Other links and lift over