rs436857

Variant names:

• chr19-18086825-G-A
• rs436857
• NM_005535.3:c.-2C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005535.3(IL12RB1):​c.-2C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,608,412 control chromosomes in the GnomAD database, including 29,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2282 hom., cov: 31)
  • Exomes 𝑓: 0.19 (27493 hom.)
• Consequence: IL12RB1 NM_005535.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.55
• Publications: 51 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-18086825-G-A is Benign according to our data. Variant chr19-18086825-G-A is described in ClinVar as Benign. ClinVar VariationId is 328605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

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.-2C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_005526.1	P42701-1
	IL12RB1	NM_005535.3	MANE Select	c.-2C>T		5_prime_UTR	Exon 1 of 17	NP_005526.1	P42701-1
	IL12RB1	NM_001440424.1		c.-2C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 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.-2C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000472165.2	P42701-1
	IL12RB1	ENST00000600835.6	TSL:1	c.-2C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 18	ENSP00000470788.1	P42701-1
	IL12RB1	ENST00000322153.11	TSL:1	c.-2C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000314425.5	P42701-3

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25863 AN: 151904 Hom.: 2279 Cov.: 31

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.164 AC: 39257 AN: 239968 AF XY: 0.165

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.0808

Gnomad FIN exome AF: 0.211

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.191 AC: 278309 AN: 1456390 Hom.: 27493 Cov.: 34 AF XY: 0.190 AC XY: 137292 AN XY: 724178

African (AFR) AF: 0.144 AC: 4813 AN: 33352

American (AMR) AF: 0.122 AC: 5409 AN: 44316

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 4940 AN: 26038

East Asian (EAS) AF: 0.151 AC: 5958 AN: 39566

South Asian (SAS) AF: 0.127 AC: 10891 AN: 85636

European-Finnish (FIN) AF: 0.205 AC: 10663 AN: 51964

Middle Eastern (MID) AF: 0.165 AC: 954 AN: 5768

European-Non Finnish (NFE) AF: 0.202 AC: 223840 AN: 1109584

Other (OTH) AF: 0.180 AC: 10841 AN: 60166

GnomAD4 genome AF: 0.170 AC: 25883 AN: 152022 Hom.: 2282 Cov.: 31 AF XY: 0.170 AC XY: 12639 AN XY: 74294

African (AFR) AF: 0.142 AC: 5901 AN: 41484

American (AMR) AF: 0.130 AC: 1990 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 649 AN: 3472

East Asian (EAS) AF: 0.102 AC: 527 AN: 5178

South Asian (SAS) AF: 0.132 AC: 636 AN: 4814

European-Finnish (FIN) AF: 0.217 AC: 2287 AN: 10556

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13387 AN: 67948

Other (OTH) AF: 0.164 AC: 345 AN: 2104

Alfa AF: 0.186 Hom.: 8927

Bravo AF: 0.161

Asia WGS AF: 0.119 AC: 417 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.86
DANN	Benign	0.82
PhyloP100		-1.6
PromoterAI		-0.058	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs436857; hg19: chr19-18197635; COSMIC: COSV59096447;