chr16-27403181-G-A

Position:

chr16-27403181-G-A

Variant summary

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

The NM_181079.5(IL21R):c.11G>A(p.Arg4His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,338,990 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 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 0.0086 ( 9 hom., cov: 32)

Exomes 𝑓: 0.011 ( 90 hom. )

Consequence

IL21R
NM_181079.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.20

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 (BayesDel_noAF=-0.82).

BP6

Variant 16-27403181-G-A is Benign according to our data. Variant chr16-27403181-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 626116.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL21R	NM_181078.3 linkuse as main transcript	c.-17+563G>A		intron_variant		ENST00000337929.8	NP_851564.1	Q9HBE5
IL21R	NM_181079.5 linkuse as main transcript	c.11G>A	p.Arg4His	missense_variant	2/10		NP_851565.4	Q9HBE5
IL21R	XM_011545857.4 linkuse as main transcript	c.11G>A	p.Arg4His	missense_variant	2/10		XP_011544159.1
IL21R	XM_017023257.3 linkuse as main transcript	c.-147+563G>A		intron_variant			XP_016878746.1	Q9HBE5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL21R	ENST00000337929.8 linkuse as main transcript	c.-17+563G>A		intron_variant		1	NM_181078.3	ENSP00000338010.3		Q9HBE5
IL21R	ENST00000564089 linkuse as main transcript	c.-56G>A		5_prime_UTR_variant	2/10	5		ENSP00000456707.1		Q9HBE5

Frequencies

GnomAD3 genomes

AF:

0.00862

AC:

1312

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00570

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0150

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.00709

AC:

955

AN:

134620

Hom.:

AF XY:

0.00662

AC XY:

485

AN XY:

73302

show subpopulations

Gnomad AFR exome

AF:

0.00543

Gnomad AMR exome

AF:

0.00797

Gnomad ASJ exome

AF:

0.00422

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00222

Gnomad FIN exome

AF:

0.00296

Gnomad NFE exome

AF:

0.0111

Gnomad OTH exome

AF:

0.00844

GnomAD4 exome

AF:

0.0108

AC:

12857

AN:

1186710

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

6098

AN XY:

581316

show subpopulations

Gnomad4 AFR exome

AF:

0.00536

Gnomad4 AMR exome

AF:

0.00792

Gnomad4 ASJ exome

AF:

0.00468

Gnomad4 EAS exome

AF:

0.0000916

Gnomad4 SAS exome

AF:

0.00175

Gnomad4 FIN exome

AF:

0.00373

Gnomad4 NFE exome

AF:

0.0124

Gnomad4 OTH exome

AF:

0.00925

GnomAD4 genome

AF:

0.00862

AC:

1312

AN:

152280

Hom.:

Cov.:

AF XY:

0.00830

AC XY:

618

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00570

Gnomad4 AMR

AF:

0.0150

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.0111

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00954

Hom.:

Bravo

AF:

0.00876

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	IL21R: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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_181079.4 exon 2 p.Arg4His (c.11G>A): This variant has been reported in the literature in 2 individuals with a clinical diagnosis of Common Variable Immunodeficiency Disorder (CVID) (van Schouwenburg 2015 PMID:26122175). However, this variant is present in 1% (701/65380) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/16-27414502-G-A). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.35

DANN

Benign

0.68

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