Genetic Variant NM_005535.3:c.695C>G (chr19-18075754-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005535.3(IL12RB1):c.695C>G(p.Pro232Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. P232L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

IL12RB1
NM_005535.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.42

Publications

0 publications found

Variant links:

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

IL12RB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.757

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL12RB1	NM_005535.3	MANE Select	c.695C>G	p.Pro232Arg	missense	Exon 7 of 17	NP_005526.1
IL12RB1	NM_001290024.2		c.815C>G	p.Pro272Arg	missense	Exon 8 of 18	NP_001276953.1
IL12RB1	NM_001440424.1		c.695C>G	p.Pro232Arg	missense	Exon 7 of 17	NP_001427353.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.695C>G	p.Pro232Arg	missense	Exon 7 of 17	ENSP00000472165.2
IL12RB1	ENST00000600835.6	TSL:1	c.695C>G	p.Pro232Arg	missense	Exon 8 of 18	ENSP00000470788.1
IL12RB1	ENST00000322153.11	TSL:1	c.695C>G	p.Pro232Arg	missense	Exon 7 of 10	ENSP00000314425.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.0092

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.3

PhyloP100

4.4

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.24

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.57

MutPred

0.36

Loss of catalytic residue at P232 (P = 0.0151)

MVP

0.77

MPC

0.48

ClinPred

0.98

GERP RS

4.5

Varity_R

0.15

gMVP

0.44

Mutation Taster

=41/59

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over