rs147215816

Variant names:

• chr19-18080970-C-A
• rs147215816
• NM_005535.3:c.271G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-18080970-C-A
• chr19-18080970-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005535.3(IL12RB1):​c.271G>T​(p.Ala91Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A91T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IL12RB1 NM_005535.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.714
• Publications: 6 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11952764).

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.271G>T	p.Ala91Ser	missense	Exon 4 of 17	NP_005526.1
	IL12RB1	NM_001290024.2		c.391G>T	p.Ala131Ser	missense	Exon 5 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.271G>T	p.Ala91Ser	missense	Exon 4 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.271G>T	p.Ala91Ser	missense	Exon 4 of 17	ENSP00000472165.2
	IL12RB1	ENST00000600835.6	TSL:1	c.271G>T	p.Ala91Ser	missense	Exon 5 of 18	ENSP00000470788.1
	IL12RB1	ENST00000322153.11	TSL:1	c.271G>T	p.Ala91Ser	missense	Exon 4 of 10	ENSP00000314425.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250756 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461202 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726876

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111852

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.27
DANN	Benign	0.28
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0089	N
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.71
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.041
Sift4G	Benign	0.77	T
Polyphen		0.024	B
Vest4		0.12
MutPred		0.34		Gain of glycosylation at A91 (P = 0.0649)
MVP		0.54
MPC		0.084
ClinPred		0.021	T
GERP RS		-0.16
Varity_R		0.026
gMVP		0.23
Mutation Taster		=99/1	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: rs147215816; hg19: chr19-18191780;