19-18069603-C-G

Variant names:

• chr19-18069603-C-G
• rs401502
• NM_005535.3:c.1132G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005535.3(IL12RB1):​c.1132G>C​(p.Gly378Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,612,144 control chromosomes in the GnomAD database, including 77,178 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G378W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.28 (6170 hom., cov: 33)
  • Exomes 𝑓: 0.31 (71008 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.86
• Publications: 60 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=0.0019493997).
• BP6: Variant 19-18069603-C-G is Benign according to our data. Variant chr19-18069603-C-G is described in ClinVar as Benign. ClinVar VariationId is 328587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.358 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.1132G>C	p.Gly378Arg	missense	Exon 10 of 17	NP_005526.1	P42701-1
	IL12RB1	NM_001290024.2		c.1252G>C	p.Gly418Arg	missense	Exon 11 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.1153G>C	p.Gly385Arg	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.1132G>C	p.Gly378Arg	missense	Exon 10 of 17	ENSP00000472165.2	P42701-1
	IL12RB1	ENST00000600835.6	TSL:1	c.1132G>C	p.Gly378Arg	missense	Exon 11 of 18	ENSP00000470788.1	P42701-1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42056 AN: 152042 Hom.: 6156 Cov.: 33

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.277

GnomAD2 exomes AF: 0.282 AC: 69853 AN: 247766 AF XY: 0.286

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.165

Gnomad ASJ exome AF: 0.336

Gnomad EAS exome AF: 0.355

Gnomad FIN exome AF: 0.322

Gnomad NFE exome AF: 0.321

Gnomad OTH exome AF: 0.282

GnomAD4 exome AF: 0.309 AC: 450439 AN: 1459984 Hom.: 71008 Cov.: 36 AF XY: 0.307 AC XY: 223346 AN XY: 726364

African (AFR) AF: 0.196 AC: 6561 AN: 33474

American (AMR) AF: 0.171 AC: 7633 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 8704 AN: 26128

East Asian (EAS) AF: 0.388 AC: 15389 AN: 39690

South Asian (SAS) AF: 0.231 AC: 19888 AN: 86242

European-Finnish (FIN) AF: 0.322 AC: 16802 AN: 52136

Middle Eastern (MID) AF: 0.300 AC: 1731 AN: 5762

European-Non Finnish (NFE) AF: 0.320 AC: 355308 AN: 1111490

Other (OTH) AF: 0.305 AC: 18423 AN: 60350

GnomAD4 genome AF: 0.277 AC: 42101 AN: 152160 Hom.: 6170 Cov.: 33 AF XY: 0.278 AC XY: 20644 AN XY: 74380

African (AFR) AF: 0.201 AC: 8345 AN: 41532

American (AMR) AF: 0.216 AC: 3292 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1130 AN: 3472

East Asian (EAS) AF: 0.372 AC: 1920 AN: 5168

South Asian (SAS) AF: 0.239 AC: 1155 AN: 4834

European-Finnish (FIN) AF: 0.337 AC: 3569 AN: 10576

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.321 AC: 21794 AN: 67982

Other (OTH) AF: 0.281 AC: 595 AN: 2116

Alfa AF: 0.302 Hom.: 4820

Bravo AF: 0.264

TwinsUK AF: 0.312 AC: 1157

ALSPAC AF: 0.322 AC: 1242

ESP6500AA AF: 0.197 AC: 796

ESP6500EA AF: 0.309 AC: 2582

ExAC AF: 0.283 AC: 34291

Asia WGS AF: 0.327 AC: 1137 AN: 3478

EpiCase AF: 0.322

EpiControl AF: 0.315

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.0050
DANN	Benign	0.49
DEOGEN2	Benign	0.085	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.9
PrimateAI	Benign	0.23	T
Sift4G	Benign	0.35	T
Polyphen		0.0030	B
Vest4		0.043
MutPred		0.11		Gain of solvent accessibility (P = 0.1319)
MPC		0.10
ClinPred		0.000035	T
GERP RS		-4.1
Varity_R		0.029
gMVP		0.34
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: rs401502; hg19: chr19-18180413; COSMIC: COSV59097331; COSMIC: COSV59097331;