Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005535.3(IL12RB1):c.1719C>T(p.Ala573Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,563,308 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 20 hom. )

Consequence

IL12RB1
NM_005535.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.05

Publications

1 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 19-18061194-G-A is Benign according to our data. Variant chr19-18061194-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 522257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.05 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00321 (488/152026) while in subpopulation AMR AF = 0.00583 (89/15260). AF 95% confidence interval is 0.00485. There are 2 homozygotes in GnomAd4. There are 232 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.1719C>T	p.Ala573Ala	synonymous	Exon 15 of 17	NP_005526.1
IL12RB1	NM_001290024.2		c.1839C>T	p.Ala613Ala	synonymous	Exon 16 of 18	NP_001276953.1
IL12RB1	NM_001440424.1		c.1740C>T	p.Ala580Ala	synonymous	Exon 15 of 17	NP_001427353.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.1719C>T	p.Ala573Ala	synonymous	Exon 15 of 17	ENSP00000472165.2
	IL12RB1	ENST00000600835.6	TSL:1	c.1719C>T	p.Ala573Ala	synonymous	Exon 16 of 18	ENSP00000470788.1

Frequencies

GnomAD3 genomes

AF:

0.00321

AC:

487

AN:

151934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00584

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0000949

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00478

Gnomad OTH

AF:

0.00576

GnomAD2 exomes

AF:

0.00301

AC:

595

AN:

197688

AF XY:

0.00317

show subpopulations

Gnomad AFR exome

AF:

0.00127

Gnomad AMR exome

AF:

0.00278

Gnomad ASJ exome

AF:

0.00113

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000214

Gnomad NFE exome

AF:

0.00473

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00401

AC:

5656

AN:

1411282

Hom.:

Cov.:

AF XY:

0.00393

AC XY:

2754

AN XY:

700950

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

32390

American (AMR)

AF:

0.00294

AC:

112

AN:

38076

Ashkenazi Jewish (ASJ)

AF:

0.00107

AC:

AN:

25326

East Asian (EAS)

AF:

0.0000259

AC:

AN:

38548

South Asian (SAS)

AF:

0.00223

AC:

182

AN:

81434

European-Finnish (FIN)

AF:

0.000368

AC:

AN:

51648

Middle Eastern (MID)

AF:

0.00616

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00467

AC:

5038

AN:

1079554

Other (OTH)

AF:

0.00353

AC:

207

AN:

58628

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

235

469

704

938

1173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

182

364

546

728

910

<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:

0.00321

AC:

488

AN:

152026

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

232

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

41494

American (AMR)

AF:

0.00583

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00270

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0000949

AC:

AN:

10538

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00478

AC:

325

AN:

67976

Other (OTH)

AF:

0.00571

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

109

136

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:

0.00444

Hom.:

Bravo

AF:

0.00321

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency 27A (2)

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.13

(source)

DANN

Benign

0.44

PhyloP100

-3.1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_005535.3:c.1719C>T

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over