NM_005535.3:c.1172C>T

Variant names:

• chr19-18069563-G-A
• rs140254802
• NM_005535.3:c.1172C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005535.3(IL12RB1):​c.1172C>T​(p.Pro391Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,610,118 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P391P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4 O:1
• Conservation: PhyloP100: -6.21
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008534402).
• BP6: Variant 19-18069563-G-A is Benign according to our data. Variant chr19-18069563-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474975.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00119 (181/152356) while in subpopulation NFE AF = 0.00194 (132/68034). AF 95% confidence interval is 0.00167. There are 1 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.1172C>T	p.Pro391Leu	missense	Exon 10 of 17	NP_005526.1	P42701-1
	IL12RB1	NM_001290024.2		c.1292C>T	p.Pro431Leu	missense	Exon 11 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.1193C>T	p.Pro398Leu	missense	Exon 10 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.1172C>T	p.Pro391Leu	missense	Exon 10 of 17	ENSP00000472165.2	P42701-1
	IL12RB1	ENST00000600835.6	TSL:1	c.1172C>T	p.Pro391Leu	missense	Exon 11 of 18	ENSP00000470788.1	P42701-1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152238 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00101 AC: 246 AN: 244446 AF XY: 0.00102

Gnomad AFR exome AF: 0.000520

Gnomad AMR exome AF: 0.000988

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00178

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.00188 AC: 2747 AN: 1457762 Hom.: 3 Cov.: 31 AF XY: 0.00183 AC XY: 1325 AN XY: 725352

African (AFR) AF: 0.000448 AC: 15 AN: 33472

American (AMR) AF: 0.000985 AC: 44 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86232

European-Finnish (FIN) AF: 0.0000802 AC: 4 AN: 49880

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5696

European-Non Finnish (NFE) AF: 0.00233 AC: 2595 AN: 1111678

Other (OTH) AF: 0.00138 AC: 83 AN: 60330

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152356 Hom.: 1 Cov.: 32 AF XY: 0.000980 AC XY: 73 AN XY: 74498

African (AFR) AF: 0.000649 AC: 27 AN: 41594

American (AMR) AF: 0.00118 AC: 18 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00194 AC: 132 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00171 Hom.: 3

Bravo AF: 0.00138

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000746 AC: 3

ESP6500EA AF: 0.00157 AC: 13

ExAC AF: 0.000918 AC: 111

ClinVar

ClinVar submissions

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)
-	-	2	not provided (3)
-	-	1	IL12RB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.0040
DANN	Benign	0.68
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.67	N
PhyloP100		-6.2
PrimateAI	Benign	0.23	T
Sift4G	Uncertain	0.054	T
Polyphen		0.014	B
Vest4		0.091
MVP		0.53
MPC		0.086
ClinPred		0.0086	T
GERP RS		-6.2
Varity_R		0.025
gMVP		0.29
Mutation Taster		=96/4	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: rs140254802; hg19: chr19-18180373;