rs1555498519

Variant names:

• chr16-27446060-T-C
• rs1555498519
• NM_181078.3:c.839T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_181078.3(IL21R):​c.839T>C​(p.Leu280Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IL21R NM_181078.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.75
• Publications: 0 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, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL21R	NM_181078.3	MANE Select	c.839T>C	p.Leu280Pro	missense	Exon 8 of 9	NP_851564.1	Q9HBE5
	IL21R	NM_181079.5		c.905T>C	p.Leu302Pro	missense	Exon 9 of 10	NP_851565.4
	IL21R	NM_021798.4		c.839T>C	p.Leu280Pro	missense	Exon 8 of 9	NP_068570.1	Q9HBE5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL21R	ENST00000337929.8	TSL:1 MANE Select	c.839T>C	p.Leu280Pro	missense	Exon 8 of 9	ENSP00000338010.3	Q9HBE5
	IL21R	ENST00000395754.4	TSL:1	c.839T>C	p.Leu280Pro	missense	Exon 8 of 9	ENSP00000379103.4	Q9HBE5
	IL21R	ENST00000564089.5	TSL:5	c.839T>C	p.Leu280Pro	missense	Exon 9 of 10	ENSP00000456707.1	Q9HBE5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461496 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727052

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111844

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cryptosporidiosis-chronic cholangitis-liver disease syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.021	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		4.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.81		Gain of relative solvent accessibility (P = 0.0215)
MVP		0.93
MPC		1.2
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.90
gMVP		0.91
Mutation Taster		=48/52	disease causing

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: rs1555498519; hg19: chr16-27457381;