rs200875188

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. 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. 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
• Publications: 6 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

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.1295C>T	p.Thr432Met	missense	Exon 11 of 17	NP_005526.1	P42701-1
	IL12RB1	NM_001290024.2		c.1415C>T	p.Thr472Met	missense	Exon 12 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.1316C>T	p.Thr439Met	missense	Exon 11 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.1295C>T	p.Thr432Met	missense	Exon 11 of 17	ENSP00000472165.2	P42701-1
	IL12RB1	ENST00000600835.6	TSL:1	c.1295C>T	p.Thr432Met	missense	Exon 12 of 18	ENSP00000470788.1	P42701-1

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

GnomAD2 exomes AF: 0.000213 AC: 53 AN: 249158 AF XY: 0.000163

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 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

African (AFR) AF: 0.00152 AC: 51 AN: 33472

American (AMR) AF: 0.0000895 AC: 4 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39692

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86246

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53400

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111450

Other (OTH) AF: 0.000249 AC: 15 AN: 60354

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

African (AFR) AF: 0.00186 AC: 77 AN: 41322

American (AMR) AF: 0.000197 AC: 3 AN: 15196

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

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67950

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000217 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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	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	0.19
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	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
MetaSVM	Uncertain	0.098	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.9
PrimateAI	Benign	0.42	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	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
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

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