rs52822694

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_181078.3(IL21R):c.824G>A(p.Arg275Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00974 in 1,613,584 control chromosomes in the GnomAD database, including 106 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R275G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0067 ( 7 hom., cov: 32)

Exomes 𝑓: 0.010 ( 99 hom. )

Consequence

IL21R
NM_181078.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: -0.817

Variant links:

Genes affected

IL21R (HGNC:6006): (interleukin 21 receptor) The protein encoded by this gene is a cytokine receptor for interleukin 21 (IL21). It belongs to the type I cytokine receptors, and has been shown to form a heterodimeric receptor complex with the common gamma-chain, a receptor subunit also shared by the receptors for interleukin 2, 4, 7, 9, and 15. This receptor transduces the growth promoting signal of IL21, and is important for the proliferation and differentiation of T cells, B cells, and natural killer (NK) cells. The ligand binding of this receptor leads to the activation of multiple downstream signaling molecules, including JAK1, JAK3, STAT1, and STAT3. Knockout studies of a similar gene in mouse suggest a role for this gene in regulating immunoglobulin production. Three alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2010]

IL21R links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005239427).

BP6

Variant 16-27446045-G-A is Benign according to our data. Variant chr16-27446045-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252799.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=2}.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL21R	NM_181078.3 linkuse as main transcript	c.824G>A	p.Arg275Gln	missense_variant	8/9	ENST00000337929.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL21R	ENST00000337929.8 linkuse as main transcript	c.824G>A	p.Arg275Gln	missense_variant	8/9	1	NM_181078.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00672

AC:

1021

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00511

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00255

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.00560

AC:

1404

AN:

250642

Hom.:

AF XY:

0.00551

AC XY:

747

AN XY:

135496

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.00451

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00115

Gnomad FIN exome

AF:

0.00301

Gnomad NFE exome

AF:

0.00954

Gnomad OTH exome

AF:

0.00739

GnomAD4 exome

AF:

0.0101

AC:

14702

AN:

1461426

Hom.:

Cov.:

AF XY:

0.00986

AC XY:

7165

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.00459

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00128

Gnomad4 FIN exome

AF:

0.00307

Gnomad4 NFE exome

AF:

0.0122

Gnomad4 OTH exome

AF:

0.00901

GnomAD4 genome

AF:

0.00671

AC:

1021

AN:

152158

Hom.:

Cov.:

AF XY:

0.00629

AC XY:

468

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00222

Gnomad4 AMR

AF:

0.00510

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00255

Gnomad4 NFE

AF:

0.0118

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00852

Hom.:

Bravo

AF:

0.00663

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0153

AC:

ESP6500AA

AF:

0.00319

AC:

ESP6500EA

AF:

0.0116

AC:

100

ExAC

AF:

0.00528

AC:

641

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0109

EpiControl

AF:

0.0103

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	IL21R: BP4, BS1, BS2 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Nov 24, 2015

- -

IgE responsiveness, atopic;C3554687:Cryptosporidiosis-chronic cholangitis-liver disease syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

IL21R NM_021798.3 exon 8 p.Arg275Gln (c.824G>A): This variant has not been reported in the literature but is present in 0.9% (1254/128760) of European alleles, including 9 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/16-27457366-G-A). This variant is present in ClinVar (Variation ID: 252799). This variant amino acid Glutamine (Gln) is present in >10 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Cryptosporidiosis-chronic cholangitis-liver disease syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.41

DANN

Benign

0.87

DEOGEN2

Benign

0.058

T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.21

.;.;T

MetaRNN

Benign

0.0052

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;L;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

0.55

N;N;N

REVEL

Benign

0.0070

Sift

Benign

0.61

T;T;T

Sift4G

Benign

0.41

T;T;T

Polyphen

0.026

B;B;B

Vest4

0.14

MVP

0.47

MPC

0.32

ClinPred

0.0018

GERP RS

-8.8

Varity_R

0.033

gMVP

0.053

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over