rs200875188

Variant names:

• chr19-18068421-G-A
• rs200875188
• NM_005535.3:c.1295C>T

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 rank	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.1295C>T	p.Thr432Met	missense_variant	Exon 11 of 17	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.1295C>T	p.Thr432Met	missense_variant	Exon 11 of 17	1	NM_005535.3	ENSP00000472165.2
IL12RB1	ENST00000600835.6	c.1295C>T	p.Thr432Met	missense_variant	Exon 12 of 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

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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;