19-18061194-G-A

Variant names:

• chr19-18061194-G-A
• rs17885102
• NM_005535.3:c.1719C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001290024.2(IL12RB1):​c.1839C>T​(p.Ala613Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,563,308 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (20 hom.)
• Consequence: IL12RB1 NM_001290024.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.05
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-18061194-G-A is Benign according to our data. Variant chr19-18061194-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 522257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00321 (488/152026) while in subpopulation AMR AF = 0.00583 (89/15260). AF 95% confidence interval is 0.00485. There are 2 homozygotes in GnomAd4. There are 232 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	NM_005535.3	MANE Select	c.1719C>T	p.Ala573Ala	synonymous	Exon 15 of 17	NP_005526.1
	IL12RB1	NM_001290024.2		c.1839C>T	p.Ala613Ala	synonymous	Exon 16 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.1740C>T	p.Ala580Ala	synonymous	Exon 15 of 17	NP_001427353.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.1719C>T	p.Ala573Ala	synonymous	Exon 15 of 17	ENSP00000472165.2
	IL12RB1	ENST00000600835.6	TSL:1	c.1719C>T	p.Ala573Ala	synonymous	Exon 16 of 18	ENSP00000470788.1

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 487 AN: 151934 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00584

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00478

Gnomad OTH AF: 0.00576

GnomAD2 exomes AF: 0.00301 AC: 595 AN: 197688 AF XY: 0.00317

Gnomad AFR exome AF: 0.00127

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00113

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000214

Gnomad NFE exome AF: 0.00473

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00401 AC: 5656 AN: 1411282 Hom.: 20 Cov.: 27 AF XY: 0.00393 AC XY: 2754 AN XY: 700950

African (AFR) AF: 0.00108 AC: 35 AN: 32390

American (AMR) AF: 0.00294 AC: 112 AN: 38076

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 27 AN: 25326

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38548

South Asian (SAS) AF: 0.00223 AC: 182 AN: 81434

European-Finnish (FIN) AF: 0.000368 AC: 19 AN: 51648

Middle Eastern (MID) AF: 0.00616 AC: 35 AN: 5678

European-Non Finnish (NFE) AF: 0.00467 AC: 5038 AN: 1079554

Other (OTH) AF: 0.00353 AC: 207 AN: 58628

GnomAD4 genome AF: 0.00321 AC: 488 AN: 152026 Hom.: 2 Cov.: 32 AF XY: 0.00312 AC XY: 232 AN XY: 74294

African (AFR) AF: 0.00104 AC: 43 AN: 41494

American (AMR) AF: 0.00583 AC: 89 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4810

European-Finnish (FIN) AF: 0.0000949 AC: 1 AN: 10538

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00478 AC: 325 AN: 67976

Other (OTH) AF: 0.00571 AC: 12 AN: 2102

Alfa AF: 0.00444 Hom.: 6

Bravo AF: 0.00321

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Immunodeficiency 27A (2)
-	-	2	Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.13
DANN	Benign	0.44
PhyloP100		-3.1
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: rs17885102; hg19: chr19-18172004;