19-18082167-G-C

Variant names:

• chr19-18082167-G-C
• rs11575925
• NM_005535.3:c.222C>G

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.222C>G​(p.Ser74Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,610,222 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0029 (13 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.531
• Publications: 10 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 (MetaRNN=0.0109061).
• BP6: Variant 19-18082167-G-C is Benign according to our data. Variant chr19-18082167-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 425167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00196 (299/152228) while in subpopulation NFE AF = 0.0031 (211/68018). AF 95% confidence interval is 0.00276. There are 0 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.222C>G	p.Ser74Arg	missense	Exon 3 of 17	NP_005526.1	P42701-1
	IL12RB1	NM_001290024.2		c.342C>G	p.Ser114Arg	missense	Exon 4 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.222C>G	p.Ser74Arg	missense	Exon 3 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.222C>G	p.Ser74Arg	missense	Exon 3 of 17	ENSP00000472165.2	P42701-1
	IL12RB1	ENST00000600835.6	TSL:1	c.222C>G	p.Ser74Arg	missense	Exon 4 of 18	ENSP00000470788.1	P42701-1
	IL12RB1	ENST00000322153.11	TSL:1	c.222C>G	p.Ser74Arg	missense	Exon 3 of 10	ENSP00000314425.5	P42701-3

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 299 AN: 152110 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00206 AC: 516 AN: 250694 AF XY: 0.00218

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.00300

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.00288 AC: 4194 AN: 1457994 Hom.: 13 Cov.: 30 AF XY: 0.00295 AC XY: 2143 AN XY: 725526

African (AFR) AF: 0.000539 AC: 18 AN: 33400

American (AMR) AF: 0.000313 AC: 14 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00305 AC: 263 AN: 86106

European-Finnish (FIN) AF: 0.00333 AC: 178 AN: 53382

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.00324 AC: 3593 AN: 1108612

Other (OTH) AF: 0.00209 AC: 126 AN: 60270

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152228 Hom.: 0 Cov.: 31 AF XY: 0.00177 AC XY: 132 AN XY: 74444

African (AFR) AF: 0.000554 AC: 23 AN: 41552

American (AMR) AF: 0.000393 AC: 6 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4818

European-Finnish (FIN) AF: 0.00405 AC: 43 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00310 AC: 211 AN: 68018

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00238 Hom.: 0

Bravo AF: 0.00147

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00182 AC: 221

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.53
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.18
Sift4G	Uncertain	0.011	D
Polyphen		0.87	P
Vest4		0.32
MutPred		0.49		Gain of MoRF binding (P = 0.0779)
MVP		0.85
MPC		0.10
ClinPred		0.032	T
GERP RS		-1.2
Varity_R		0.12
gMVP		0.67
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs11575925; hg19: chr19-18192977; COSMIC: COSV105227065; COSMIC: COSV105227065;