19-18059998-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_005535.3(IL12RB1):c.1879G>A(p.Glu627Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000592 in 1,600,834 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (1 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0750

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.005658984).
• BP6: Variant 19-18059998-C-T is Benign according to our data. Variant chr19-18059998-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 328576.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 = 0.000453 (69/152310) while in subpopulation SAS AF= 0.00311 (15/4828). AF 95% confidence interval is 0.00191. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB1	NM_005535.3	c.1879G>A	p.Glu627Lys	missense_variant	16/17	ENST00000593993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB1	ENST00000593993.7	c.1879G>A	p.Glu627Lys	missense_variant	16/17	1	NM_005535.3	P1
IL12RB1	ENST00000600835.6	c.1879G>A	p.Glu627Lys	missense_variant	17/18	1		P1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000831 AC: 199 AN: 239360 Hom.: 1 AF XY: 0.00103 AC XY: 134 AN XY: 129872

Gnomad AFR exome AF: 0.000140

Gnomad AMR exome AF: 0.000150

Gnomad ASJ exome AF: 0.000723

Gnomad EAS exome AF: 0.0000570

Gnomad SAS exome AF: 0.00262

Gnomad FIN exome AF: 0.000568

Gnomad NFE exome AF: 0.000766

Gnomad OTH exome AF: 0.00221

GnomAD4 exome AF: 0.000607 AC: 879 AN: 1448524 Hom.: 1 Cov.: 29 AF XY: 0.000709 AC XY: 511 AN XY: 720582

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.000137

Gnomad4 ASJ exome AF: 0.000813

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00251

Gnomad4 FIN exome AF: 0.000678

Gnomad4 NFE exome AF: 0.000501

Gnomad4 OTH exome AF: 0.000568

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74472

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000740 Hom.: 0

Bravo AF: 0.000518

ESP6500AA AF: 0.000252 AC: 1

ESP6500EA AF: 0.000361 AC: 3

ExAC AF: 0.000993 AC: 120

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	7.7
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.024	N
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.83	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
Sift4G	Uncertain	0.022	D;D
Polyphen		0.89	P;P
Vest4		0.068
MVP		0.84
MPC		0.10
ClinPred		0.033	T
GERP RS		1.4
Varity_R		0.046
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs143367415; hg19: chr19-18170808;