rs52822694

Variant names:

• chr16-27446045-G-A
• rs52822694
• NM_181078.3:c.824G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-27446045-G-A
• chr16-27446045-G-C
• chr16-27446045-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000337929.8(IL21R):​c.824G>A​(p.Arg275Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00974 in 1,613,584 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. R275G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0067 (7 hom., cov: 32)
  • Exomes 𝑓: 0.010 (99 hom.)
• Consequence: IL21R ENST00000337929.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.817
• Publications: 12 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.005239427).
• BP6: Variant 16-27446045-G-A is Benign according to our data. Variant chr16-27446045-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 252799.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000337929.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL21R	NM_181078.3	MANE Select	c.824G>A	p.Arg275Gln	missense	Exon 8 of 9	NP_851564.1
	IL21R	NM_181079.5		c.890G>A	p.Arg297Gln	missense	Exon 9 of 10	NP_851565.4
	IL21R	NM_021798.4		c.824G>A	p.Arg275Gln	missense	Exon 8 of 9	NP_068570.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL21R	ENST00000337929.8	TSL:1 MANE Select	c.824G>A	p.Arg275Gln	missense	Exon 8 of 9	ENSP00000338010.3
	IL21R	ENST00000395754.4	TSL:1	c.824G>A	p.Arg275Gln	missense	Exon 8 of 9	ENSP00000379103.4
	IL21R	ENST00000564089.5	TSL:5	c.824G>A	p.Arg275Gln	missense	Exon 9 of 10	ENSP00000456707.1

Frequencies

GnomAD3 genomes AF: 0.00672 AC: 1021 AN: 152040 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00560 AC: 1404 AN: 250642 AF XY: 0.00551

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00301

Gnomad NFE exome AF: 0.00954

Gnomad OTH exome AF: 0.00739

GnomAD4 exome AF: 0.0101 AC: 14702 AN: 1461426 Hom.: 99 Cov.: 31 AF XY: 0.00986 AC XY: 7165 AN XY: 727024

African (AFR) AF: 0.00149 AC: 50 AN: 33474

American (AMR) AF: 0.00459 AC: 205 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00128 AC: 110 AN: 86200

European-Finnish (FIN) AF: 0.00307 AC: 164 AN: 53354

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5760

European-Non Finnish (NFE) AF: 0.0122 AC: 13609 AN: 1111762

Other (OTH) AF: 0.00901 AC: 544 AN: 60378

GnomAD4 genome AF: 0.00671 AC: 1021 AN: 152158 Hom.: 7 Cov.: 32 AF XY: 0.00629 AC XY: 468 AN XY: 74384

African (AFR) AF: 0.00222 AC: 92 AN: 41500

American (AMR) AF: 0.00510 AC: 78 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4812

European-Finnish (FIN) AF: 0.00255 AC: 27 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0118 AC: 805 AN: 68006

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00829 Hom.: 17

Bravo AF: 0.00663

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.00319 AC: 14

ESP6500EA AF: 0.0116 AC: 100

ExAC AF: 0.00528 AC: 641

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.0103

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cryptosporidiosis-chronic cholangitis-liver disease syndrome (1)
-	1	-	IgE responsiveness, atopic;C3554687:Cryptosporidiosis-chronic cholangitis-liver disease syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.41
DANN	Benign	0.87
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.82
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.0070
Sift	Benign	0.61	T
Sift4G	Benign	0.41	T
Polyphen		0.026	B
Vest4		0.14
MVP		0.47
MPC		0.32
ClinPred		0.0018	T
GERP RS		-8.8
Varity_R		0.033
gMVP		0.053
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs52822694; hg19: chr16-27457366; COSMIC: COSV61972191; COSMIC: COSV61972191;