16-27443104-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_181078.3(IL21R):c.495C>A(p.Asp165Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000658 in 1,611,240 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

IL21R
NM_181078.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.158

Publications

1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

IL21R links:

ENSG00000308281 (HGNC:):

ENSG00000308281 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.060138643).

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
IL21R	NM_181078.3	MANE Select	c.495C>A	p.Asp165Glu	missense	Exon 5 of 9	NP_851564.1
IL21R	NM_181079.5		c.561C>A	p.Asp187Glu	missense	Exon 6 of 10	NP_851565.4
IL21R	NM_021798.4		c.495C>A	p.Asp165Glu	missense	Exon 5 of 9	NP_068570.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL21R	ENST00000337929.8	TSL:1 MANE Select	c.495C>A	p.Asp165Glu	missense	Exon 5 of 9	ENSP00000338010.3
IL21R	ENST00000395754.4	TSL:1	c.495C>A	p.Asp165Glu	missense	Exon 5 of 9	ENSP00000379103.4
IL21R	ENST00000564089.5	TSL:5	c.495C>A	p.Asp165Glu	missense	Exon 6 of 10	ENSP00000456707.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000523

AC:

AN:

248372

AF XY:

0.0000671

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000672

AC:

AN:

1459026

Hom.:

Cov.:

AF XY:

0.0000689

AC XY:

AN XY:

725744

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33382

American (AMR)

AF:

0.0000226

AC:

AN:

44252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25942

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.00

AC:

AN:

85764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000846

AC:

AN:

1110676

Other (OTH)

AF:

0.0000498

AC:

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41516

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

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:

0.000174

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cryptosporidiosis-chronic cholangitis-liver disease syndrome

Uncertain:1

Jul 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 165 of the IL21R protein (p.Asp165Glu). This variant is present in population databases (rs779790998, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with IL21R-related conditions. ClinVar contains an entry for this variant (Variation ID: 540992). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Inborn genetic diseases

Uncertain:1

May 24, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.561C>A (p.D187E) alteration is located in exon 6 (coding exon 5) of the IL21R gene. This alteration results from a C to A substitution at nucleotide position 561, causing the aspartic acid (D) at amino acid position 187 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.10

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.46

M_CAP

Benign

0.026

MetaRNN

Benign

0.060

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.2

PhyloP100

-0.16

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.44

REVEL

Benign

0.026

Sift

Benign

0.34

Sift4G

Benign

0.41

Polyphen

0.010

Vest4

0.048

MutPred

0.30

Loss of MoRF binding (P = 0.1092)

MVP

0.59

MPC

0.26

ClinPred

0.059

GERP RS

2.7

Varity_R

0.14

gMVP

0.11

Mutation Taster

=77/23

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over