rs200875188

Positions:

• chr19-18068421-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_005535.3(IL12RB1):​c.1295C>T​(p.Thr432Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,612,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.91

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 Benign. Variant got -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048459023).
• BP6: Variant 19-18068421-G-A is Benign according to our data. Variant chr19-18068421-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 474977.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000553 (84/151774) while in subpopulation AFR AF= 0.00186 (77/41322). AF 95% confidence interval is 0.00153. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.1295C>T	p.Thr432Met	missense_variant	11/17	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.1295C>T	p.Thr432Met	missense_variant	11/17	1	NM_005535.3	ENSP00000472165.2
IL12RB1	ENST00000600835.6	c.1295C>T	p.Thr432Met	missense_variant	12/18	1		ENSP00000470788.1

Frequencies

GnomAD3 genomes AF: 0.000553 AC: 84 AN: 151774 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000213 AC: 53 AN: 249158 Hom.: 0 AF XY: 0.000163 AC XY: 22 AN XY: 135198

Gnomad AFR exome AF: 0.00245

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000671 AC: 98 AN: 1461224 Hom.: 0 Cov.: 30 AF XY: 0.0000633 AC XY: 46 AN XY: 726944

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000553 AC: 84 AN: 151774 Hom.: 0 Cov.: 29 AF XY: 0.000567 AC XY: 42 AN XY: 74096

Gnomad4 AFR AF: 0.00186

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000103 Hom.: 1

Bravo AF: 0.000646

ESP6500AA AF: 0.00278 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000289 AC: 35

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;T
Eigen	Benign	0.069
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.82	.;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.048	T;T
MetaSVM	Uncertain	0.098	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Benign	0.42	T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.26
MVP		0.90
MPC		0.43
ClinPred		0.048	T
GERP RS		3.5
Varity_R		0.35
gMVP		0.39

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: rs200875188; hg19: chr19-18179231; COSMIC: COSV59096032; COSMIC: COSV59096032;