Genetic Variant IL21R:c.-17+562C>T (chr16-27403180-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_181079.5(IL21R):c.10C>T(p.Arg4Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000262 in 1,181,842 control chromosomes in the GnomAD database, including 2 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000026 ( 2 hom. )

Consequence

IL21R
NM_181079.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.464

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL21R	NM_181078.3 link	c.-17+562C>T		intron_variant	Intron 1 of 8	ENST00000337929.8	NP_851564.1	Q9HBE5
IL21R	NM_181079.5 link	c.10C>T	p.Arg4Cys	missense_variant	Exon 2 of 10		NP_851565.4	Q9HBE5
IL21R	XM_011545857.4 link	c.10C>T	p.Arg4Cys	missense_variant	Exon 2 of 10		XP_011544159.1
IL21R	XM_017023257.3 link	c.-147+562C>T		intron_variant	Intron 1 of 9		XP_016878746.1	Q9HBE5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
IL21R	ENST00000337929.8 link	c.-17+562C>T	intron_variant	Intron 1 of 8	1	NM_181078.3	ENSP00000338010.3	Q9HBE5
IL21R	ENST00000564089 link	c.-57C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 10	5		ENSP00000456707.1	Q9HBE5
IL21R	ENST00000564089 link	c.-57C>T	5_prime_UTR_variant	Exon 2 of 10	5		ENSP00000456707.1	Q9HBE5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000743

AC:

AN:

134604

Hom.:

AF XY:

0.0000136

AC XY:

AN XY:

73288

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000409

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000262

AC:

AN:

1181842

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

579208

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.0000334

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000458

Gnomad4 SAS exome

AF:

0.0000131

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000212

Gnomad4 OTH exome

AF:

0.000305

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cryptosporidiosis-chronic cholangitis-liver disease syndrome

Uncertain:1

Nov 15, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

4.0

DANN

Benign

0.71

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