rs137946070

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_181078.3(IL21R):c.137C>T(p.Thr46Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00562 in 1,611,872 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T46T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0046 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 38 hom. )

Consequence

IL21R
NM_181078.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -3.64

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
cryptosporidiosis-chronic cholangitis-liver disease syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

IL21R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00445199).

BP6

Variant 16-27434434-C-T is Benign according to our data. Variant chr16-27434434-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402977.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181078.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL21R	NM_181078.3	MANE Select	c.137C>T	p.Thr46Met	missense	Exon 3 of 9	NP_851564.1	Q9HBE5
IL21R	NM_181079.5		c.203C>T	p.Thr68Met	missense	Exon 4 of 10	NP_851565.4
IL21R	NM_021798.4		c.137C>T	p.Thr46Met	missense	Exon 3 of 9	NP_068570.1	Q9HBE5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL21R	ENST00000337929.8	TSL:1 MANE Select	c.137C>T	p.Thr46Met	missense	Exon 3 of 9	ENSP00000338010.3	Q9HBE5
IL21R	ENST00000395754.4	TSL:1	c.137C>T	p.Thr46Met	missense	Exon 3 of 9	ENSP00000379103.4	Q9HBE5
IL21R	ENST00000564089.5	TSL:5	c.137C>T	p.Thr46Met	missense	Exon 4 of 10	ENSP00000456707.1	Q9HBE5

Frequencies

GnomAD3 genomes

AF:

0.00460

AC:

700

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00694

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00446

AC:

1119

AN:

250822

AF XY:

0.00470

show subpopulations

Gnomad AFR exome

AF:

0.000985

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.0200

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00191

Gnomad NFE exome

AF:

0.00642

Gnomad OTH exome

AF:

0.00474

GnomAD4 exome

AF:

0.00573

AC:

8356

AN:

1459546

Hom.:

Cov.:

AF XY:

0.00562

AC XY:

4082

AN XY:

726184

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

33414

American (AMR)

AF:

0.00206

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0181

AC:

473

AN:

26116

East Asian (EAS)

AF:

0.000176

AC:

AN:

39688

South Asian (SAS)

AF:

0.000777

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

53252

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00656

AC:

7282

AN:

1110074

Other (OTH)

AF:

0.00506

AC:

305

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

370

741

1111

1482

1852

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

270

540

810

1080

1350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00460

AC:

700

AN:

152326

Hom.:

Cov.:

AF XY:

0.00395

AC XY:

294

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

41560

American (AMR)

AF:

0.00340

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3470

East Asian (EAS)

AF:

0.000772

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00694

AC:

472

AN:

68028

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

122

162

203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00633

Hom.:

Bravo

AF:

0.00436

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00651

AC:

ExAC

AF:

0.00419

AC:

509

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00660

EpiControl

AF:

0.00492

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cryptosporidiosis-chronic cholangitis-liver disease syndrome (2)

IL21R-related disorder (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

0.047

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.13

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.43

M_CAP

Benign

0.070

MetaRNN

Benign

0.0045

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.76

PhyloP100

-3.6

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.85

REVEL

Benign

0.25

Sift

Benign

0.12

Sift4G

Benign

0.18

Polyphen

0.30

Vest4

0.23

MVP

0.47

MPC

0.32

ClinPred

0.0036

GERP RS

-7.0

Varity_R

0.11

gMVP

0.60

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over