16-27434434-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

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=0.00445199).

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 id is 402977.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr16-27434434-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL21R	NM_181078.3 link	c.137C>T	p.Thr46Met	missense_variant	Exon 3 of 9	ENST00000337929.8	NP_851564.1	Q9HBE5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IL21R	ENST00000337929.8 link	c.137C>T	p.Thr46Met	missense_variant	Exon 3 of 9	1	NM_181078.3	ENSP00000338010.3	Q9HBE5
IL21R	ENST00000395754.4 link	c.137C>T	p.Thr46Met	missense_variant	Exon 3 of 9	1		ENSP00000379103.4	Q9HBE5
IL21R	ENST00000564089.5 link	c.137C>T	p.Thr46Met	missense_variant	Exon 4 of 10	5		ENSP00000456707.1	Q9HBE5
IL21R	ENST00000697146.1 link	n.137C>T		non_coding_transcript_exon_variant	Exon 2 of 7			ENSP00000513135.1	A0A8V8TL34

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

GnomAD3 exomes

AF:

0.00446

AC:

1119

AN:

250822

Hom.:

AF XY:

0.00470

AC XY:

637

AN XY:

135592

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 SAS exome

AF:

0.000817

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

Gnomad4 AFR exome

AF:

0.00117

Gnomad4 AMR exome

AF:

0.00206

Gnomad4 ASJ exome

AF:

0.0181

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.000777

Gnomad4 FIN exome

AF:

0.00169

Gnomad4 NFE exome

AF:

0.00656

Gnomad4 OTH exome

AF:

0.00506

GnomAD4 genome

AF:

0.00460

AC:

700

AN:

152326

Hom.:

Cov.:

AF XY:

0.00395

AC XY:

294

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00156

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.0225

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00188

Gnomad4 NFE

AF:

0.00694

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00660

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cryptosporidiosis-chronic cholangitis-liver disease syndrome

Benign:2

May 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

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: Gene associated with autosomal recessive primary immunodeficiency, but no suspicious second variant and no information on this variant. -

not provided

Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IL21R: BP4, BS2 -

IL21R-related disorder

Benign:1

May 14, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

0.047

DANN

Benign

0.75

DEOGEN2

Benign

0.13

T;T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.43

.;.;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.76

N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.85

N;N;N

REVEL

Benign

0.25

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.18

T;T;T

Polyphen

0.30

B;B;B

Vest4

0.23

MVP

0.47

MPC

0.32

ClinPred

0.0036

GERP RS

-7.0

Varity_R

0.11

gMVP

0.60

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