Genetic Variant IL10RB:p.Trp8Cys (chr21-33266489-G-T) – 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_000628.5(IL10RB):c.24G>T(p.Trp8Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,390,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

IL10RB
NM_000628.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60

Publications

0 publications found

Variant links:

Genes affected

IL10RB (HGNC:5965): (interleukin 10 receptor subunit beta) The protein encoded by this gene belongs to the cytokine receptor family. It is an accessory chain essential for the active interleukin 10 receptor complex. Coexpression of this and IL10RA proteins has been shown to be required for IL10-induced signal transduction. This gene and three other interferon receptor genes, IFAR2, IFNAR1, and IFNGR2, form a class II cytokine receptor gene cluster located in a small region on chromosome 21. [provided by RefSeq, Jul 2008]

IL10RB links:

IFNAR2-IL10RB (HGNC:):

IFNAR2-IL10RB links:

IL10RB-DT (HGNC:44303): (IL10RB divergent transcript)

IL10RB-DT links:

Genome browser will be placed here

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, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL10RB	NM_000628.5 link	c.24G>T	p.Trp8Cys	missense_variant	Exon 1 of 7	ENST00000290200.7	NP_000619.3	Q08334

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL10RB	ENST00000290200.7 link	c.24G>T	p.Trp8Cys	missense_variant	Exon 1 of 7	1	NM_000628.5	ENSP00000290200.2		Q08334
IFNAR2-IL10RB	ENST00000433395.7 link	c.710-1905G>T		intron_variant	Intron 7 of 12	5		ENSP00000388223.3		H0Y3Z8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.19e-7

AC:

AN:

1390358

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31574

American (AMR)

AF:

0.00

AC:

AN:

35802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35888

South Asian (SAS)

AF:

0.00

AC:

AN:

79226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4424

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1079242

Other (OTH)

AF:

0.00

AC:

AN:

57834

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 22, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.24G>T (p.W8C) alteration is located in exon 1 (coding exon 1) of the IL10RB gene. This alteration results from a G to T substitution at nucleotide position 24, causing the tryptophan (W) at amino acid position 8 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.5

PhyloP100

2.6

PROVEAN

Benign

-2.3

REVEL

Benign

0.23

Sift

Benign

0.063

Sift4G

Uncertain

0.021

Polyphen

0.99

Vest4

0.57

MutPred

0.61

Loss of sheet (P = 0.0011);

MVP

0.59

MPC

0.51

ClinPred

0.75

GERP RS

3.7

PromoterAI

-0.076

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.84

Mutation Taster

=79/21

polymorphism

(source)

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

Publications

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21-33266489-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over