21-33288184-G-A

Variant names:

• chr21-33288184-G-A
• rs1058861
• NM_000628.5:c.727G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000628.5(IL10RB):​c.727G>A​(p.Ala243Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A243S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: IL10RB NM_000628.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.638
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038517922).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL10RB	NM_000628.5	MANE Select	c.727G>A	p.Ala243Thr	missense	Exon 6 of 7	NP_000619.3
	IFNAR2-IL10RB	NM_001414505.1		c.1387G>A	p.Ala463Thr	missense	Exon 12 of 13	NP_001401434.1
	IL10RB	NM_001405850.1		c.727G>A	p.Ala243Thr	missense	Exon 6 of 7	NP_001392779.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL10RB	ENST00000290200.7	TSL:1 MANE Select	c.727G>A	p.Ala243Thr	missense	Exon 6 of 7	ENSP00000290200.2
	IFNAR2-IL10RB	ENST00000433395.7	TSL:5	c.1387G>A	p.Ala463Thr	missense	Exon 12 of 13	ENSP00000388223.3
	IL10RB	ENST00000896213.1		c.721G>A	p.Ala241Thr	missense	Exon 6 of 7	ENSP00000566272.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152104 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000835 AC: 21 AN: 251490 AF XY: 0.0000883

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000150 AC: 219 AN: 1461752 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 98 AN XY: 727196

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000182 AC: 202 AN: 1111888

Other (OTH) AF: 0.000132 AC: 8 AN: 60394

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152104 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74288

African (AFR) AF: 0.0000483 AC: 2 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00000406 Hom.: 2

Bravo AF: 0.000102

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Inflammatory bowel disease 25 (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.5
DANN	Benign	0.88
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.74	N
PhyloP100		0.64
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.022
Sift	Benign	0.39	T
Sift4G	Benign	0.39	T
Polyphen		0.0020	B
Vest4		0.12
MVP		0.33
MPC		0.32
ClinPred		0.019	T
GERP RS		1.4
PromoterAI		0.0090	Neutral
Varity_R		0.031
gMVP		0.24
Mutation Taster		=93/7	polymorphism

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: rs1058861; hg19: chr21-34660489; COSMIC: COSV51615105; COSMIC: COSV51615105;