rs373545812

Variant names:

• chr19-18080980-G-A
• rs373545812
• NM_005535.3:c.261C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001290024.2(IL12RB1):​c.381C>T​(p.Cys127Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,613,070 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: IL12RB1 NM_001290024.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.870
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 19-18080980-G-A is Benign according to our data. Variant chr19-18080980-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541822.
• BP7: Synonymous conserved (PhyloP=0.87 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290024.2. 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.261C>T	p.Cys87Cys	synonymous	Exon 4 of 17	NP_005526.1
	IL12RB1	NM_001290024.2		c.381C>T	p.Cys127Cys	synonymous	Exon 5 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.261C>T	p.Cys87Cys	synonymous	Exon 4 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.261C>T	p.Cys87Cys	synonymous	Exon 4 of 17	ENSP00000472165.2
	IL12RB1	ENST00000600835.6	TSL:1	c.261C>T	p.Cys87Cys	synonymous	Exon 5 of 18	ENSP00000470788.1
	IL12RB1	ENST00000322153.11	TSL:1	c.261C>T	p.Cys87Cys	synonymous	Exon 4 of 10	ENSP00000314425.5

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152182 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000351 AC: 88 AN: 250424 AF XY: 0.000347

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000636

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000316 AC: 462 AN: 1460770 Hom.: 2 Cov.: 32 AF XY: 0.000334 AC XY: 243 AN XY: 726692

African (AFR) AF: 0.0000598 AC: 2 AN: 33464

American (AMR) AF: 0.000134 AC: 6 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 24 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52902

Middle Eastern (MID) AF: 0.000366 AC: 2 AN: 5458

European-Non Finnish (NFE) AF: 0.000367 AC: 408 AN: 1111840

Other (OTH) AF: 0.000331 AC: 20 AN: 60336

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152300 Hom.: 0 Cov.: 31 AF XY: 0.000349 AC XY: 26 AN XY: 74488

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.000196 AC: 3 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000381 Hom.: 0

Bravo AF: 0.000484

EpiCase AF: 0.000709

EpiControl AF: 0.00119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	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
BayesDel_noAF	Benign	-0.59
CADD	Benign	3.1
DANN	Benign	0.54
PhyloP100		0.87
Mutation Taster		=100/0	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: rs373545812; hg19: chr19-18191790;