rs121434495

Positions:

• chr19-18075857-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000593993.7(IL12RB1):​c.592T>C​(p.Cys198Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IL12RB1 ENST00000593993.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.405

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain Fibronectin type-III 2 (size 92) in uniprot entity I12R1_HUMAN there are 19 pathogenic changes around while only 2 benign (90%) in ENST00000593993.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 19-18075857-A-G is Pathogenic according to our data. Variant chr19-18075857-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 8038.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-18075857-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.592T>C	p.Cys198Arg	missense_variant	7/17	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.592T>C	p.Cys198Arg	missense_variant	7/17	1	NM_005535.3	ENSP00000472165	P1
IL12RB1	ENST00000600835.6	c.592T>C	p.Cys198Arg	missense_variant	8/18	1		ENSP00000470788	P1
IL12RB1	ENST00000322153.11	c.592T>C	p.Cys198Arg	missense_variant	7/10	1		ENSP00000314425

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.22	T;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.64	.;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.6	.;.;D
REVEL	Uncertain	0.55
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.82
MutPred		0.86		Gain of phosphorylation at S195 (P = 0.0793);Gain of phosphorylation at S195 (P = 0.0793);Gain of phosphorylation at S195 (P = 0.0793);
MVP		0.91
MPC		0.58
ClinPred		0.82	D
GERP RS		-1.2
Varity_R		0.36
gMVP		0.41

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

LitVar

Other links and lift over

dbSNP: rs121434495; hg19: chr19-18186667;