rs145590794

Variant names:

• chr19-18060064-C-A
• rs145590794
• NM_005535.3:c.1813G>T
• IL12RB1 p.Val605Leu

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005535.3(IL12RB1):​c.1813G>T​(p.Val605Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,603,074 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (4 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.436
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073914826).
• BP6: Variant 19-18060064-C-A is Benign according to our data. Variant chr19-18060064-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 541821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00205 (313/152346) while in subpopulation NFE AF = 0.00273 (186/68032). AF 95% confidence interval is 0.00241. There are 1 homozygotes in GnomAd4. There are 165 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.1813G>T	p.Val605Leu	missense	Exon 16 of 17	NP_005526.1	P42701-1
	IL12RB1	NM_001290024.2		c.1933G>T	p.Val645Leu	missense	Exon 17 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.1834G>T	p.Val612Leu	missense	Exon 16 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.1813G>T	p.Val605Leu	missense	Exon 16 of 17	ENSP00000472165.2	P42701-1
	IL12RB1	ENST00000600835.6	TSL:1	c.1813G>T	p.Val605Leu	missense	Exon 17 of 18	ENSP00000470788.1	P42701-1

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 313 AN: 152228 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00838

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00273

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00179 AC: 435 AN: 242972 AF XY: 0.00185

Gnomad AFR exome AF: 0.000204

Gnomad AMR exome AF: 0.000767

Gnomad ASJ exome AF: 0.000308

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00559

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.00238 AC: 3457 AN: 1450728 Hom.: 4 Cov.: 28 AF XY: 0.00241 AC XY: 1737 AN XY: 721982

African (AFR) AF: 0.000150 AC: 5 AN: 33280

American (AMR) AF: 0.000904 AC: 40 AN: 44252

Ashkenazi Jewish (ASJ) AF: 0.000541 AC: 14 AN: 25872

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.000422 AC: 36 AN: 85302

European-Finnish (FIN) AF: 0.00599 AC: 319 AN: 53248

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5734

European-Non Finnish (NFE) AF: 0.00266 AC: 2938 AN: 1103388

Other (OTH) AF: 0.00173 AC: 104 AN: 60034

GnomAD4 genome AF: 0.00205 AC: 313 AN: 152346 Hom.: 1 Cov.: 32 AF XY: 0.00221 AC XY: 165 AN XY: 74500

African (AFR) AF: 0.000457 AC: 19 AN: 41582

American (AMR) AF: 0.000785 AC: 12 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00838 AC: 89 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00273 AC: 186 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00235 Hom.: 1

Bravo AF: 0.00144

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency (2)
-	-	1	IL12RB1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.44
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.28	T
Varity_R		0.052
gMVP		0.14
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs145590794;

hg19: chr19-18170874;