16-27403181-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_181078.3(IL21R):c.-17+563G>A variant causes a intron 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. 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_181078.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.20

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]

ACMG classification

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: {Uncertain_significance=1, Benign=1, Likely_benign=1}.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL21R	NM_181078.3	c.-17+563G>A		intron_variant		ENST00000337929.8
IL21R	NM_181079.5	c.11G>A	p.Arg4His	missense_variant	2/10
IL21R	XM_011545857.4	c.11G>A	p.Arg4His	missense_variant	2/10
IL21R	XM_017023257.3	c.-147+563G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL21R	ENST00000337929.8	c.-17+563G>A		intron_variant		1	NM_181078.3	P1
IL21R	ENST00000564089.5	c.-56G>A		5_prime_UTR_variant	2/10	5		P1

Frequencies

GnomAD3 genomes AF: 0.00862 AC: 1312 AN: 152162 Hom.: 9 Cov.: 32

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.: 4 AF XY: 0.00662 AC XY: 485 AN XY: 73302

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.: 90 Cov.: 26 AF XY: 0.0105 AC XY: 6098 AN XY: 581316

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.: 9 Cov.: 32 AF XY: 0.00830 AC XY: 618 AN XY: 74458

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.: 0

Bravo AF: 0.00876

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	IL21R: BS1, BS2 -

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

Other links and lift over

dbSNP: rs117535117; hg19: chr16-27414502; COSMIC: COSV61971315;