19-18076318-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_005535.3(IL12RB1):​c.559G>A​(p.Gly187Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,422,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G187G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3303283).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	NM_005535.3	MANE Select	c.559G>A	p.Gly187Arg	missense	Exon 6 of 17	NP_005526.1
	IL12RB1	NM_001290024.2		c.679G>A	p.Gly227Arg	missense	Exon 7 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.559G>A	p.Gly187Arg	missense	Exon 6 of 17	NP_001427353.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.559G>A	p.Gly187Arg	missense	Exon 6 of 17	ENSP00000472165.2
	IL12RB1	ENST00000600835.6	TSL:1	c.559G>A	p.Gly187Arg	missense	Exon 7 of 18	ENSP00000470788.1
	IL12RB1	ENST00000322153.11	TSL:1	c.559G>A	p.Gly187Arg	missense	Exon 6 of 10	ENSP00000314425.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000518 AC: 13 AN: 251192 AF XY: 0.0000589

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 20 AN: 1270680 Hom.: 0 Cov.: 20 AF XY: 0.0000187 AC XY: 12 AN XY: 641980

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

American (AMR) AF: 0.000225 AC: 10 AN: 44486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 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: 0.0000188 AC: 1 AN: 53140

Middle Eastern (MID) AF: 0.000185 AC: 1 AN: 5412

European-Non Finnish (NFE) AF: 0.00000747 AC: 7 AN: 937446

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

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74482

African (AFR) AF: 0.0000241 AC: 1 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.022	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.30
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.35
Sift4G	Uncertain	0.010	D
Polyphen		0.65	P
Vest4		0.44
MutPred		0.51		Loss of catalytic residue at G187 (P = 0.0679)
MVP		0.94
MPC		0.18
ClinPred		0.15	T
GERP RS		1.5
Varity_R		0.083
gMVP		0.48
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;