rs3213119

Variant names:

Variant summary

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

The NM_002187.3(IL12B):c.892G>T(p.Val298Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,614,030 control chromosomes in the GnomAD database, including 649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 40 hom., cov: 33)

Exomes 𝑓: 0.027 ( 609 hom. )

Consequence

IL12B
NM_002187.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.06

Publications

34 publications found

Variant links:

Genes affected

IL12B (HGNC:5970): (interleukin 12B) This gene encodes a subunit of interleukin 12, a cytokine that acts on T and natural killer cells, and has a broad array of biological activities. Interleukin 12 is a disulfide-linked heterodimer composed of the 40 kD cytokine receptor like subunit encoded by this gene, and a 35 kD subunit encoded by IL12A. This cytokine is expressed by activated macrophages that serve as an essential inducer of Th1 cells development. This cytokine has been found to be important for sustaining a sufficient number of memory/effector Th1 cells to mediate long-term protection to an intracellular pathogen. Overexpression of this gene was observed in the central nervous system of patients with multiple sclerosis (MS), suggesting a role of this cytokine in the pathogenesis of the disease. The promoter polymorphism of this gene has been reported to be associated with the severity of atopic and non-atopic asthma in children. [provided by RefSeq, Jul 2008]

IL12B Gene-Disease associations (from GenCC):

Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

IL12B links:

IL12B-AS1 (HGNC:58156):

IL12B-AS1 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=0.0036674142).

BP6

Variant 5-159316780-C-A is Benign according to our data. Variant chr5-159316780-C-A is described in ClinVar as Benign. ClinVar VariationId is 352572.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 = 0.0212 (3224/152302) while in subpopulation NFE AF = 0.0304 (2067/68028). AF 95% confidence interval is 0.0293. There are 40 homozygotes in GnomAd4. There are 1578 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 40 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002187.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12B	NM_002187.3	MANE Select	c.892G>T	p.Val298Phe	missense	Exon 7 of 8	NP_002178.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL12B	ENST00000231228.3	TSL:1 MANE Select	c.892G>T	p.Val298Phe	missense	Exon 7 of 8	ENSP00000231228.2	P29460
IL12B	ENST00000696750.1		c.262G>T	p.Val88Phe	missense	Exon 4 of 5	ENSP00000512849.1	A0A8Q3WML5
IL12B	ENST00000696751.1		n.*387G>T		non_coding_transcript_exon	Exon 6 of 7	ENSP00000512850.1	A0A8Q3SJ12

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3224

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00610

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0289

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0291

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0304

Gnomad OTH

AF:

0.0244

GnomAD2 exomes

AF:

0.0207

AC:

5150

AN:

248422

AF XY:

0.0203

show subpopulations

Gnomad AFR exome

AF:

0.00527

Gnomad AMR exome

AF:

0.0209

Gnomad ASJ exome

AF:

0.0152

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0303

Gnomad NFE exome

AF:

0.0300

Gnomad OTH exome

AF:

0.0207

GnomAD4 exome

AF:

0.0273

AC:

39960

AN:

1461728

Hom.:

609

Cov.:

AF XY:

0.0263

AC XY:

19159

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.00508

AC:

170

AN:

33478

American (AMR)

AF:

0.0217

AC:

970

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

429

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00254

AC:

219

AN:

86258

European-Finnish (FIN)

AF:

0.0290

AC:

1547

AN:

53350

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0316

AC:

35098

AN:

1111922

Other (OTH)

AF:

0.0236

AC:

1428

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

2086

4171

6257

8342

10428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1318

2636

3954

5272

6590

<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:

0.0212

AC:

3224

AN:

152302

Hom.:

Cov.:

AF XY:

0.0212

AC XY:

1578

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00609

AC:

253

AN:

41570

American (AMR)

AF:

0.0288

AC:

441

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0159

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00290

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0291

AC:

309

AN:

10612

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0304

AC:

2067

AN:

68028

Other (OTH)

AF:

0.0241

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

168

335

503

670

838

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0273

Hom.:

289

Bravo

AF:

0.0210

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0298

AC:

115

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.0303

AC:

261

ExAC

AF:

0.0205

AC:

2485

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0286

EpiControl

AF:

0.0313

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.56

MutationAssessor

Pathogenic

3.2

PhyloP100

1.1

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.13

Sift

Uncertain

0.021

Sift4G

Uncertain

0.0050

Polyphen

0.98

Vest4

0.24

MPC

0.90

ClinPred

0.066

GERP RS

5.7

Varity_R

0.64

gMVP

0.69

Mutation Taster

=83/17

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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