rs3093385

chr16-27448620-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_181078.3(IL21R):c.954C>G(p.Ser318Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000777 in 1,613,116 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0042 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: IL21R NM_181078.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.123

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-AS1 (HGNC:27551): (IL21R antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032425523).
• BP6: Variant 16-27448620-C-G is Benign according to our data. Variant chr16-27448620-C-G is described in ClinVar as [Benign]. Clinvar id is 541000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-27448620-C-G is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL21R	NM_181078.3	c.954C>G	p.Ser318Arg	missense_variant	9/9	ENST00000337929.8
IL21R-AS1	NR_037158.1	n.1664G>C		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL21R	ENST00000337929.8	c.954C>G	p.Ser318Arg	missense_variant	9/9	1	NM_181078.3	P1
IL21R-AS1	ENST00000563191.1	n.1664G>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00418 AC: 636 AN: 152178 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00112 AC: 278 AN: 248394 Hom.: 0 AF XY: 0.000895 AC XY: 121 AN XY: 135162

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.000423 AC: 618 AN: 1460820 Hom.: 3 Cov.: 31 AF XY: 0.000359 AC XY: 261 AN XY: 726730

Gnomad4 AFR exome AF: 0.0155

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00418 AC: 636 AN: 152296 Hom.: 3 Cov.: 33 AF XY: 0.00399 AC XY: 297 AN XY: 74466

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.00468

ESP6500AA AF: 0.0121 AC: 53

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00140 AC: 170

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cryptosporidiosis-chronic cholangitis-liver disease syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	5.7
Dann	Benign	0.95
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.28	N
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.042
Sift	Uncertain	0.029	D;D;D
Sift4G	Uncertain	0.032	D;D;D
Polyphen		0.66	P;P;P
Vest4		0.060
MutPred		0.12		Gain of catalytic residue at S318 (P = 0.0165);Gain of catalytic residue at S318 (P = 0.0165);Gain of catalytic residue at S318 (P = 0.0165);
MVP		0.14
MPC		0.69
ClinPred		0.021	T
GERP RS		0.22
Varity_R		0.12
gMVP		0.43

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: rs3093385; hg19: chr16-27459941;