chr19-18062235-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005535.3(IL12RB1):​c.1661G>C​(p.Gly554Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G554E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IL12RB1
NM_005535.3 missense

Scores

2
7
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.83

Publications

9 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.879

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IL12RB1NM_005535.3 linkc.1661G>C p.Gly554Ala missense_variant Exon 14 of 17 ENST00000593993.7 NP_005526.1 P42701-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IL12RB1ENST00000593993.7 linkc.1661G>C p.Gly554Ala missense_variant Exon 14 of 17 1 NM_005535.3 ENSP00000472165.2 P42701-1
IL12RB1ENST00000600835.6 linkc.1661G>C p.Gly554Ala missense_variant Exon 15 of 18 1 ENSP00000470788.1 P42701-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000402
AC:
1
AN:
248610
AF XY:
0.00000741
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000887
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461012
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
726812
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33448
American (AMR)
AF:
0.00
AC:
0
AN:
44652
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26100
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39684
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86248
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53230
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1111538
Other (OTH)
AF:
0.00
AC:
0
AN:
60348
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000827
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Uncertain
0.028
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.66
D;D
Eigen
Benign
0.17
Eigen_PC
Benign
0.091
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.82
.;T
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.88
D;D
MetaSVM
Uncertain
-0.22
T
MutationAssessor
Benign
1.9
L;L
PhyloP100
2.8
PrimateAI
Uncertain
0.48
T
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.74
MutPred
0.33
Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);
MVP
0.87
MPC
0.48
ClinPred
0.89
D
GERP RS
2.5
Varity_R
0.67
gMVP
0.48
Mutation Taster
=82/18
polymorphism

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

Other links and lift over

dbSNP: rs369861364; hg19: chr19-18173045; API