Genetic Variant NM_005535.3:c.139C>T (chr19-18082250-G-A) – 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.139C>T(p.Pro47Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00234 in 1,610,706 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 59 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 45 hom. )

Consequence

IL12RB1
NM_005535.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.37

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: 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004633844).

BP6

Variant 19-18082250-G-A is Benign according to our data. Variant chr19-18082250-G-A is described in ClinVar as Benign. ClinVar VariationId is 328604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1998/152230) while in subpopulation AFR AF = 0.0456 (1896/41534). AF 95% confidence interval is 0.0439. There are 59 homozygotes in GnomAd4. There are 949 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 59 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	UniProt
IL12RB1	NM_005535.3	MANE Select	c.139C>T	p.Pro47Ser	missense	Exon 3 of 17	NP_005526.1	P42701-1
IL12RB1	NM_001290024.2		c.259C>T	p.Pro87Ser	missense	Exon 4 of 18	NP_001276953.1
IL12RB1	NM_001440424.1		c.139C>T	p.Pro47Ser	missense	Exon 3 of 17	NP_001427353.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.139C>T	p.Pro47Ser	missense	Exon 3 of 17	ENSP00000472165.2	P42701-1
IL12RB1	ENST00000600835.6	TSL:1	c.139C>T	p.Pro47Ser	missense	Exon 4 of 18	ENSP00000470788.1	P42701-1
IL12RB1	ENST00000322153.11	TSL:1	c.139C>T	p.Pro47Ser	missense	Exon 3 of 10	ENSP00000314425.5	P42701-3

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1991

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0456

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00333

AC:

827

AN:

248038

AF XY:

0.00256

show subpopulations

Gnomad AFR exome

AF:

0.0457

Gnomad AMR exome

AF:

0.00222

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.000992

GnomAD4 exome

AF:

0.00122

AC:

1778

AN:

1458476

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

770

AN XY:

725682

show subpopulations

African (AFR)

AF:

0.0436

AC:

1457

AN:

33420

American (AMR)

AF:

0.00252

AC:

112

AN:

44494

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.0000582

AC:

AN:

85934

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53314

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1109560

Other (OTH)

AF:

0.00275

AC:

166

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

164

246

328

410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.0131

AC:

1998

AN:

152230

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

949

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0456

AC:

1896

AN:

41534

American (AMR)

AF:

0.00484

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68014

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

194

291

388

485

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00692

Hom.:

Bravo

AF:

0.0148

ESP6500AA

AF:

0.0477

AC:

210

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00428

AC:

520

Asia WGS

AF:

0.00173

AC:

AN:

3478

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 IL12RB1 deficiency (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0046

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.7

PhyloP100

4.4

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.24

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.60

MVP

0.88

MPC

0.47

ClinPred

0.059

GERP RS

2.8

Varity_R

0.28

gMVP

0.85

Mutation Taster

=95/5

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

Computational scores

Splicing

Publications

Other links and lift over