chr21-33268483-A-G

Variant names:

• chr21-33268483-A-G
• rs2834167
• NM_000628.5:c.139A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000628.5(IL10RB):​c.139A>G​(p.Lys47Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,613,124 control chromosomes in the GnomAD database, including 66,866 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (5821 hom., cov: 32)
  • Exomes 𝑓: 0.28 (61045 hom.)
• Consequence: IL10RB NM_000628.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.677
• Publications: 117 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.5644255E-4).
• BP6: Variant 21-33268483-A-G is Benign according to our data. Variant chr21-33268483-A-G is described in ClinVar as Benign. ClinVar VariationId is 16923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000628.5. 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
	IL10RB	NM_000628.5	MANE Select	c.139A>G	p.Lys47Glu	missense	Exon 2 of 7	NP_000619.3
	IFNAR2-IL10RB	NM_001414505.1		c.799A>G	p.Lys267Glu	missense	Exon 8 of 13	NP_001401434.1
	IL10RB	NM_001405850.1		c.139A>G	p.Lys47Glu	missense	Exon 2 of 7	NP_001392779.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL10RB	ENST00000290200.7	TSL:1 MANE Select	c.139A>G	p.Lys47Glu	missense	Exon 2 of 7	ENSP00000290200.2
	IFNAR2-IL10RB	ENST00000433395.7	TSL:5	c.799A>G	p.Lys267Glu	missense	Exon 8 of 13	ENSP00000388223.3
	IL10RB	ENST00000609556.3	TSL:5	c.139A>G	p.Lys47Glu	missense	Exon 2 of 7	ENSP00000489965.2

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38639 AN: 152118 Hom.: 5821 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.253

GnomAD2 exomes AF: 0.330 AC: 83064 AN: 251442 AF XY: 0.330

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.502

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.569

Gnomad FIN exome AF: 0.320

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.320

GnomAD4 exome AF: 0.278 AC: 405506 AN: 1460888 Hom.: 61045 Cov.: 33 AF XY: 0.281 AC XY: 204127 AN XY: 726848

African (AFR) AF: 0.119 AC: 3985 AN: 33470

American (AMR) AF: 0.491 AC: 21959 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 7353 AN: 26128

East Asian (EAS) AF: 0.555 AC: 22042 AN: 39684

South Asian (SAS) AF: 0.381 AC: 32889 AN: 86238

European-Finnish (FIN) AF: 0.320 AC: 17081 AN: 53418

Middle Eastern (MID) AF: 0.340 AC: 1956 AN: 5750

European-Non Finnish (NFE) AF: 0.253 AC: 280663 AN: 1111130

Other (OTH) AF: 0.291 AC: 17578 AN: 60350

GnomAD4 genome AF: 0.254 AC: 38649 AN: 152236 Hom.: 5821 Cov.: 32 AF XY: 0.263 AC XY: 19580 AN XY: 74422

African (AFR) AF: 0.126 AC: 5252 AN: 41562

American (AMR) AF: 0.386 AC: 5899 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 984 AN: 3472

East Asian (EAS) AF: 0.569 AC: 2951 AN: 5186

South Asian (SAS) AF: 0.392 AC: 1892 AN: 4822

European-Finnish (FIN) AF: 0.324 AC: 3430 AN: 10590

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17398 AN: 67996

Other (OTH) AF: 0.255 AC: 539 AN: 2112

Alfa AF: 0.266 Hom.: 26542

Bravo AF: 0.256

TwinsUK AF: 0.253 AC: 939

ALSPAC AF: 0.258 AC: 994

ESP6500AA AF: 0.131 AC: 576

ESP6500EA AF: 0.257 AC: 2214

ExAC AF: 0.319 AC: 38727

Asia WGS AF: 0.465 AC: 1615 AN: 3478

EpiCase AF: 0.275

EpiControl AF: 0.275

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, associated with susceptibility to hepatitis

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 75% of patients studied by a panel of primary immunodeficiencies. Number of patients: 72. Only high quality variants are reported.

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Inflammatory bowel disease 25 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Hepatitis B virus, susceptibility to Other:1

Jun 13, 2006

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.067
Eigen_PC	Benign	0.010
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.00076	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.68
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.10
Sift	Benign	0.084	T
Sift4G	Benign	0.29	T
Polyphen		0.58	P
Vest4		0.043
MPC		0.50
ClinPred		0.015	T
GERP RS		2.6
Varity_R		0.39
gMVP		0.62
Mutation Taster		=80/20	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2834167; hg19: chr21-34640788; COSMIC: COSV51614715; COSMIC: COSV51614715;