rs564884307

Variant names:

• chr19-18076318-C-A
• rs564884307
• NM_005535.3:c.559G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-18076318-C-A
• chr19-18076318-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005535.3(IL12RB1):​c.559G>T​(p.Gly187*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000708 in 1,270,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G187G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: IL12RB1 NM_005535.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.299
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-18076318-C-A is Pathogenic according to our data. Variant chr19-18076318-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 576660.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.559G>T	p.Gly187*	stop_gained	Exon 6 of 17	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.559G>T	p.Gly187*	stop_gained	Exon 6 of 17	1	NM_005535.3	ENSP00000472165.2
IL12RB1	ENST00000600835.6	c.559G>T	p.Gly187*	stop_gained	Exon 7 of 18	1		ENSP00000470788.1
IL12RB1	ENST00000322153.11	c.559G>T	p.Gly187*	stop_gained	Exon 6 of 10	1		ENSP00000314425.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251192 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000708 AC: 9 AN: 1270680 Hom.: 0 Cov.: 20 AF XY: 0.0000109 AC XY: 7 AN XY: 641980

African (AFR) AF: 0.00 AC: 0 AN: 29844

American (AMR) AF: 0.00 AC: 0 AN: 44486

Ashkenazi Jewish (ASJ) AF: 0.000319 AC: 8 AN: 25056

East Asian (EAS) AF: 0.00 AC: 0 AN: 38878

South Asian (SAS) AF: 0.00 AC: 0 AN: 82462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5412

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 937446

Other (OTH) AF: 0.0000185 AC: 1 AN: 53956

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency Pathogenic:1

May 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in IL12RB1 are known to be pathogenic (PMID: 9603733, 12591909). This variant has not been reported in the literature in individuals with IL12RB1-related disease. This variant is present in population databases (rs564884307, ExAC 0.002%). This sequence change creates a premature translational stop signal (p.Gly187*) in the IL12RB1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Benign	0.18
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.29	N
PhyloP100		0.30
Vest4		0.70
GERP RS		1.5
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs564884307; hg19: chr19-18187128;