NM_005535.3:c.1048G>A

Variant names:

• chr19-18069687-C-T
• rs200811721
• NM_005535.3:c.1048G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_005535.3(IL12RB1):​c.1048G>A​(p.Gly350Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,612,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.532
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029208004).
• BP6: Variant 19-18069687-C-T is Benign according to our data. Variant chr19-18069687-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 580063.

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.1048G>A	p.Gly350Arg	missense	Exon 10 of 17	NP_005526.1
	IL12RB1	NM_001290024.2		c.1168G>A	p.Gly390Arg	missense	Exon 11 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.1069G>A	p.Gly357Arg	missense	Exon 10 of 17	NP_001427353.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.1048G>A	p.Gly350Arg	missense	Exon 10 of 17	ENSP00000472165.2
	IL12RB1	ENST00000600835.6	TSL:1	c.1048G>A	p.Gly350Arg	missense	Exon 11 of 18	ENSP00000470788.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000265 AC: 66 AN: 248882 AF XY: 0.000178

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000136 AC: 199 AN: 1460404 Hom.: 0 Cov.: 31 AF XY: 0.000110 AC XY: 80 AN XY: 726556

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.000425 AC: 19 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00413 AC: 108 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52932

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111110

Other (OTH) AF: 0.000348 AC: 21 AN: 60340

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74296

African (AFR) AF: 0.0000724 AC: 3 AN: 41412

American (AMR) AF: 0.000328 AC: 5 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.000331 Hom.: 0

Bravo AF: 0.000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.53
PrimateAI	Benign	0.28	T
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.21
MutPred		0.44		Gain of MoRF binding (P = 0.0231)
MVP		0.89
MPC		0.13
ClinPred		0.030	T
GERP RS		1.6
Varity_R		0.060
gMVP		0.44
Mutation Taster		=86/14	polymorphism

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: rs200811721; hg19: chr19-18180497; COSMIC: COSV59100370; COSMIC: COSV59100370;