19-18080970-C-T

Position:

• chr19-18080970-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005535.3(IL12RB1):​c.271G>A​(p.Ala91Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000847 in 1,613,386 control chromosomes in the GnomAD database, including 32 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A91A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00079 (30 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.714

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004359752).
• BP6: Variant 19-18080970-C-T is Benign according to our data. Variant chr19-18080970-C-T is described in ClinVar as [Benign]. Clinvar id is 328602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18080970-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00137 (209/152184) while in subpopulation EAS AF= 0.0375 (194/5172). AF 95% confidence interval is 0.0332. There are 2 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.271G>A	p.Ala91Thr	missense_variant	4/17	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.271G>A	p.Ala91Thr	missense_variant	4/17	1	NM_005535.3	ENSP00000472165.2
IL12RB1	ENST00000600835.6	c.271G>A	p.Ala91Thr	missense_variant	5/18	1		ENSP00000470788.1
IL12RB1	ENST00000322153.11	c.271G>A	p.Ala91Thr	missense_variant	4/10	1		ENSP00000314425.5
IL12RB1	ENST00000430026.7	c.283G>A	p.Ala95Thr	missense_variant	4/4	4		ENSP00000403103.3

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152066 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0380

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00349 AC: 876 AN: 250756 Hom.: 26 AF XY: 0.00331 AC XY: 449 AN XY: 135634

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0466

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000792 AC: 1158 AN: 1461202 Hom.: 30 Cov.: 32 AF XY: 0.000764 AC XY: 555 AN XY: 726876

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0268

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.000812

GnomAD4 genome AF: 0.00137 AC: 209 AN: 152184 Hom.: 2 Cov.: 31 AF XY: 0.00175 AC XY: 130 AN XY: 74408

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0375

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00138 Hom.: 7

Bravo AF: 0.00172

ExAC AF: 0.00306 AC: 371

Asia WGS AF: 0.00664 AC: 24 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

IL12RB1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.3
DANN	Benign	0.17
DEOGEN2	Benign	0.11	T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.57	.;T;T;T
MetaRNN	Benign	0.0044	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L;L;L;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.2	.;.;N;.
REVEL	Benign	0.076
Sift4G	Benign	1.0	T;T;T;.
Polyphen		0.0020	B;B;B;.
Vest4		0.068
MVP		0.58
MPC		0.082
ClinPred		0.0023	T
GERP RS		-0.16
Varity_R		0.021
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs147215816; hg19: chr19-18191780;