16-27430074-GC-AA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_181078.3(IL21R):c.3_4delinsAA(p.MetPro1_?2) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IL21R NM_181078.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL21R	NM_181078.3	c.3_4delinsAA	p.MetPro1_?2	start_lost	2/9	ENST00000337929.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL21R	ENST00000337929.8	c.3_4delinsAA	p.MetPro1_?2	start_lost	2/9	1	NM_181078.3	P1
IL21R	ENST00000395754.4	c.3_4delinsAA	p.MetPro1_?2	start_lost	2/9	1		P1
IL21R	ENST00000564089.5	c.3_4delinsAA	p.MetPro1_?2	start_lost	3/10	5		P1
IL21R	ENST00000697146.1	c.3_4delinsAA	p.MetPro1_?2	start_lost, NMD_transcript_variant	1/7

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cryptosporidiosis-chronic cholangitis-liver disease syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 18, 2018

This sequence change affects the initiator methionine of the IL21R mRNA. The next in-frame methionine is located at codon 39. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with IL21R-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the amino acids located between p.Met1 and p.Met39 is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1567364201; hg19: chr16-27441395;