19-18073507-G-A

Variant names:

• chr19-18073507-G-A
• rs79972275
• NM_005535.3:c.783+10C>T

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.783+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00913 in 1,573,350 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0095 (107 hom.)
• Consequence: IL12RB1 NM_005535.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.526
• Publications: 3 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=-0.9).
• BP6: Variant 19-18073507-G-A is Benign according to our data. Variant chr19-18073507-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00564 (858/152024) while in subpopulation SAS AF = 0.0106 (51/4810). AF 95% confidence interval is 0.00871. There are 7 homozygotes in GnomAd4. There are 378 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.783+10C>T		intron	N/A	NP_005526.1	P42701-1
	IL12RB1	NM_001290024.2		c.903+10C>T		intron	N/A	NP_001276953.1
	IL12RB1	NM_001440424.1		c.804+10C>T		intron	N/A	NP_001427353.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.783+10C>T		intron	N/A	ENSP00000472165.2	P42701-1
	IL12RB1	ENST00000600835.6	TSL:1	c.783+10C>T		intron	N/A	ENSP00000470788.1	P42701-1
	IL12RB1	ENST00000322153.11	TSL:1	c.783+10C>T		intron	N/A	ENSP00000314425.5	P42701-3

Frequencies

GnomAD3 genomes AF: 0.00565 AC: 859 AN: 151906 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00165

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.00388

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00932

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00648 AC: 1624 AN: 250570 AF XY: 0.00695

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000834

Gnomad NFE exome AF: 0.00890

Gnomad OTH exome AF: 0.00900

GnomAD4 exome AF: 0.00950 AC: 13507 AN: 1421326 Hom.: 107 Cov.: 28 AF XY: 0.00966 AC XY: 6850 AN XY: 709278

African (AFR) AF: 0.00144 AC: 47 AN: 32704

American (AMR) AF: 0.00365 AC: 163 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00325 AC: 84 AN: 25884

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.0127 AC: 1081 AN: 85418

European-Finnish (FIN) AF: 0.00142 AC: 76 AN: 53366

Middle Eastern (MID) AF: 0.0116 AC: 66 AN: 5698

European-Non Finnish (NFE) AF: 0.0106 AC: 11426 AN: 1075008

Other (OTH) AF: 0.00955 AC: 564 AN: 59062

GnomAD4 genome AF: 0.00564 AC: 858 AN: 152024 Hom.: 7 Cov.: 31 AF XY: 0.00509 AC XY: 378 AN XY: 74310

African (AFR) AF: 0.00164 AC: 68 AN: 41452

American (AMR) AF: 0.00387 AC: 59 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3464

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4810

European-Finnish (FIN) AF: 0.000945 AC: 10 AN: 10580

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

European-Non Finnish (NFE) AF: 0.00931 AC: 633 AN: 67996

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00587 Hom.: 2

Bravo AF: 0.00571

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

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)
-	-	1	IL12RB1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.26
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79972275; hg19: chr19-18184317;