NM_005535.3:c.125-117C>T

Variant names:

• chr19-18082381-G-A
• rs2305743
• NM_005535.3:c.125-117C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005535.3(IL12RB1):​c.125-117C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 707,256 control chromosomes in the GnomAD database, including 13,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (2772 hom., cov: 31)
  • Exomes 𝑓: 0.19 (10894 hom.)
• Consequence: IL12RB1 NM_005535.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.37
• Publications: 32 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-18082381-G-A is Benign according to our data. Variant chr19-18082381-G-A is described in ClinVar as Benign. ClinVar VariationId is 2688457.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.208 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	NM_005535.3	MANE Select	c.125-117C>T		intron	N/A	NP_005526.1
	IL12RB1	NM_001290024.2		c.245-117C>T		intron	N/A	NP_001276953.1
	IL12RB1	NM_001440424.1		c.125-117C>T		intron	N/A	NP_001427353.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.125-117C>T		intron	N/A	ENSP00000472165.2
	IL12RB1	ENST00000600835.6	TSL:1	c.125-117C>T		intron	N/A	ENSP00000470788.1
	IL12RB1	ENST00000322153.11	TSL:1	c.125-117C>T		intron	N/A	ENSP00000314425.5

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28405 AN: 151768 Hom.: 2768 Cov.: 31

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.183

GnomAD4 exome AF: 0.193 AC: 107155 AN: 555370 Hom.: 10894 AF XY: 0.190 AC XY: 56927 AN XY: 299526

African (AFR) AF: 0.169 AC: 2648 AN: 15710

American (AMR) AF: 0.141 AC: 4846 AN: 34350

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 3909 AN: 19688

East Asian (EAS) AF: 0.174 AC: 5482 AN: 31460

South Asian (SAS) AF: 0.126 AC: 7828 AN: 62062

European-Finnish (FIN) AF: 0.221 AC: 8653 AN: 39080

Middle Eastern (MID) AF: 0.175 AC: 699 AN: 3998

European-Non Finnish (NFE) AF: 0.211 AC: 67270 AN: 318726

Other (OTH) AF: 0.192 AC: 5820 AN: 30296

GnomAD4 genome AF: 0.187 AC: 28429 AN: 151886 Hom.: 2772 Cov.: 31 AF XY: 0.186 AC XY: 13815 AN XY: 74228

African (AFR) AF: 0.171 AC: 7090 AN: 41442

American (AMR) AF: 0.144 AC: 2203 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 679 AN: 3470

East Asian (EAS) AF: 0.108 AC: 557 AN: 5158

South Asian (SAS) AF: 0.128 AC: 618 AN: 4812

European-Finnish (FIN) AF: 0.228 AC: 2402 AN: 10532

Middle Eastern (MID) AF: 0.140 AC: 41 AN: 292

European-Non Finnish (NFE) AF: 0.211 AC: 14334 AN: 67914

Other (OTH) AF: 0.181 AC: 381 AN: 2110

Alfa AF: 0.200 Hom.: 13689

Bravo AF: 0.178

Asia WGS AF: 0.130 AC: 456 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 27. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.84
DANN	Benign	0.82
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs2305743; hg19: chr19-18193191; COSMIC: COSV59097571; COSMIC: COSV59097571;