rs11575934

Variant names:

• chr19-18075808-T-C
• rs11575934
• NM_005535.3:c.641A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_005535.3(IL12RB1):​c.641A>G​(p.Gln214Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,611,352 control chromosomes in the GnomAD database, including 75,833 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5580 hom., cov: 32)
  • Exomes 𝑓: 0.31 (70253 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.194
• Publications: 75 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005535.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0024283528).
• BP6: Variant 19-18075808-T-C is Benign according to our data. Variant chr19-18075808-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.357 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	NM_005535.3	MANE Select	c.641A>G	p.Gln214Arg	missense	Exon 7 of 17	NP_005526.1	P42701-1
	IL12RB1	NM_001290024.2		c.761A>G	p.Gln254Arg	missense	Exon 8 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.641A>G	p.Gln214Arg	missense	Exon 7 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.641A>G	p.Gln214Arg	missense	Exon 7 of 17	ENSP00000472165.2	P42701-1
	IL12RB1	ENST00000600835.6	TSL:1	c.641A>G	p.Gln214Arg	missense	Exon 8 of 18	ENSP00000470788.1	P42701-1
	IL12RB1	ENST00000322153.11	TSL:1	c.641A>G	p.Gln214Arg	missense	Exon 7 of 10	ENSP00000314425.5	P42701-3

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38637 AN: 151984 Hom.: 5570 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.261

GnomAD2 exomes AF: 0.277 AC: 69637 AN: 251238 AF XY: 0.283

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.336

Gnomad EAS exome AF: 0.354

Gnomad FIN exome AF: 0.326

Gnomad NFE exome AF: 0.321

Gnomad OTH exome AF: 0.280

GnomAD4 exome AF: 0.306 AC: 446325 AN: 1459250 Hom.: 70253 Cov.: 32 AF XY: 0.305 AC XY: 221603 AN XY: 726102

African (AFR) AF: 0.119 AC: 3983 AN: 33450

American (AMR) AF: 0.167 AC: 7458 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 8699 AN: 26120

East Asian (EAS) AF: 0.385 AC: 15281 AN: 39668

South Asian (SAS) AF: 0.230 AC: 19837 AN: 86216

European-Finnish (FIN) AF: 0.325 AC: 17360 AN: 53376

Middle Eastern (MID) AF: 0.299 AC: 1727 AN: 5768

European-Non Finnish (NFE) AF: 0.319 AC: 353920 AN: 1109604

Other (OTH) AF: 0.299 AC: 18060 AN: 60326

GnomAD4 genome AF: 0.254 AC: 38675 AN: 152102 Hom.: 5580 Cov.: 32 AF XY: 0.256 AC XY: 19037 AN XY: 74340

African (AFR) AF: 0.124 AC: 5162 AN: 41518

American (AMR) AF: 0.206 AC: 3153 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1128 AN: 3470

East Asian (EAS) AF: 0.371 AC: 1919 AN: 5168

South Asian (SAS) AF: 0.239 AC: 1153 AN: 4822

European-Finnish (FIN) AF: 0.337 AC: 3563 AN: 10580

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.320 AC: 21744 AN: 67968

Other (OTH) AF: 0.266 AC: 560 AN: 2108

Alfa AF: 0.303 Hom.: 17579

Bravo AF: 0.238

TwinsUK AF: 0.312 AC: 1158

ALSPAC AF: 0.323 AC: 1244

ESP6500AA AF: 0.131 AC: 578

ESP6500EA AF: 0.316 AC: 2715

ExAC AF: 0.276 AC: 33563

Asia WGS AF: 0.322 AC: 1121 AN: 3478

EpiCase AF: 0.321

EpiControl AF: 0.316

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency (3)
-	-	3	not specified (3)
-	-	2	Immunodeficiency 27A (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.021
DANN	Benign	0.11
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N
PhyloP100		-0.19
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.15
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.038
MPC		0.090
ClinPred		0.0042	T
GERP RS		1.7
Varity_R		0.018
gMVP		0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs11575934; hg19: chr19-18186618; COSMIC: COSV59097375;