rs56148525

Variant names:

Variant summary

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

The NM_181078.3(IL21R):c.1033G>A(p.Gly345Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,613,242 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. G345D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 9 hom. )

Consequence

IL21R
NM_181078.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 0.373

Publications

13 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 links:

IL21R-AS1 (HGNC:27551): (IL21R antisense RNA 1)

IL21R-AS1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_181078.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0034081936).

BP6

Variant 16-27448699-G-A is Benign according to our data. Variant chr16-27448699-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225037.

BS2

High Homozygotes in GnomAdExome4 at 9 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.1033G>A	p.Gly345Ser	missense	Exon 9 of 9	NP_851564.1	Q9HBE5
IL21R	NM_181079.5		c.1099G>A	p.Gly367Ser	missense	Exon 10 of 10	NP_851565.4
IL21R	NM_021798.4		c.1033G>A	p.Gly345Ser	missense	Exon 9 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.1033G>A	p.Gly345Ser	missense	Exon 9 of 9	ENSP00000338010.3	Q9HBE5
IL21R	ENST00000395754.4	TSL:1	c.1033G>A	p.Gly345Ser	missense	Exon 9 of 9	ENSP00000379103.4	Q9HBE5
IL21R	ENST00000564089.5	TSL:5	c.1033G>A	p.Gly345Ser	missense	Exon 10 of 10	ENSP00000456707.1	Q9HBE5

Frequencies

GnomAD3 genomes

AF:

0.00265

AC:

404

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00425

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:

0.00426

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00231

AC:

578

AN:

250206

AF XY:

0.00244

show subpopulations

Gnomad AFR exome

AF:

0.000807

Gnomad AMR exome

AF:

0.00324

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00374

Gnomad OTH exome

AF:

0.00327

GnomAD4 exome

AF:

0.00400

AC:

5847

AN:

1460900

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

2898

AN XY:

726760

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33480

American (AMR)

AF:

0.00376

AC:

168

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000612

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000133

AC:

AN:

52478

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00482

AC:

5361

AN:

1111974

Other (OTH)

AF:

0.00441

AC:

266

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

352

704

1055

1407

1759

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

218

436

654

872

1090

<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:

0.00265

AC:

404

AN:

152342

Hom.:

Cov.:

AF XY:

0.00260

AC XY:

194

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41570

American (AMR)

AF:

0.00425

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00426

AC:

290

AN:

68028

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00392

Hom.:

Bravo

AF:

0.00300

EpiCase

AF:

0.00442

EpiControl

AF:

0.00504

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 (3)

not provided (2)

IgE responsiveness, atopic;C3554687:Cryptosporidiosis-chronic cholangitis-liver disease syndrome (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

CADD

Benign

6.0

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.10

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.48

M_CAP

Benign

0.0058

MetaRNN

Benign

0.0034

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

0.37

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.40

REVEL

Benign

0.087

Sift

Benign

0.37

Sift4G

Benign

0.090

Varity_R

0.025

gMVP

0.31

Mutation Taster

=97/3

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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