rs121909601

Variant names:

• chr21-33279897-G-A
• rs121909601
• NM_000628.5:c.477G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-33279897-G-A
• chr21-33279897-G-C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000628.5(IL10RB):​c.477G>A​(p.Trp159*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IL10RB NM_000628.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.65
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• inflammatory bowel disease 25

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• IL10-related early-onset inflammatory bowel disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

IFNAR2-IL10RB (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-33279897-G-A is Pathogenic according to our data. Variant chr21-33279897-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16924.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL10RB	NM_000628.5	c.477G>A	p.Trp159*	stop_gained	Exon 4 of 7	ENST00000290200.7	NP_000619.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL10RB	ENST00000290200.7	c.477G>A	p.Trp159*	stop_gained	Exon 4 of 7	1	NM_000628.5	ENSP00000290200.2
IFNAR2-IL10RB	ENST00000433395.7	c.1137G>A	p.Trp379*	stop_gained	Exon 10 of 13	5		ENSP00000388223.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inflammatory bowel disease 25 Pathogenic:2

Nov 19, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 25, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp159*) in the IL10RB gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with IL10RB-related disease in one family (PMID: 19890111) and has been observed in additional individuals with IL10RB-related disease (PMID: 25373860, 27699073). ClinVar contains an entry for this variant (Variation ID: 16924). This variant has been reported to affect IL10RB protein function in patient derived cells (PMID: 19890111). Loss-of-function variants in IL10RB are known to be pathogenic (PMID: 22549091). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		5.6
Vest4		0.82
ClinPred		1.0	D
GERP RS		5.5
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs121909601; hg19: chr21-34652202;