rs4833837

chr4-122615808-G-Achr4-122615808-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021803.4(IL21):c.234C>T(p.Cys78=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 1,610,618 control chromosomes in the GnomAD database, including 417,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45989 hom., cov: 33)
  • Exomes 𝑓: 0.71 (371236 hom.)
• Consequence: IL21 NM_021803.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.583

Genes affected

IL21 (HGNC:6005): (interleukin 21) This gene encodes a member of the common-gamma chain family of cytokines with immunoregulatory activity. The encoded protein plays a role in both the innate and adaptive immune responses by inducing the differentiation, proliferation and activity of multiple target cells including macrophages, natural killer cells, B cells and cytotoxic T cells. Dysregulation of this gene plays a role in multiple immune-mediated diseases including lupus, psoriasis and chronic inflammatory diseases. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 4-122615808-G-A is Benign according to our data. Variant chr4-122615808-G-A is described in ClinVar as [Benign]. Clinvar id is 402975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.583 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL21	NM_021803.4	c.234C>T	p.Cys78=	synonymous_variant	3/5	ENST00000648588.1
IL21	NM_001207006.3	c.234C>T	p.Cys78=	synonymous_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL21	ENST00000648588.1	c.234C>T	p.Cys78=	synonymous_variant	3/5		NM_021803.4	P1
IL21	ENST00000611104.2	c.234C>T	p.Cys78=	synonymous_variant	3/4	1
IL21	ENST00000647784.1	n.86C>T		non_coding_transcript_exon_variant	2/4

Frequencies

GnomAD3 genomes AF: 0.768 AC: 116798 AN: 152028 Hom.: 45926 Cov.: 33

Gnomad AFR AF: 0.921

Gnomad AMI AF: 0.813

Gnomad AMR AF: 0.813

Gnomad ASJ AF: 0.743

Gnomad EAS AF: 0.886

Gnomad SAS AF: 0.855

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.775

GnomAD3 exomes AF: 0.744 AC: 186361 AN: 250468 Hom.: 71025 AF XY: 0.741 AC XY: 100333 AN XY: 135368

Gnomad AFR exome AF: 0.929

Gnomad AMR exome AF: 0.856

Gnomad ASJ exome AF: 0.739

Gnomad EAS exome AF: 0.887

Gnomad SAS exome AF: 0.841

Gnomad FIN exome AF: 0.550

Gnomad NFE exome AF: 0.673

Gnomad OTH exome AF: 0.716

GnomAD4 exome AF: 0.709 AC: 1033909 AN: 1458472 Hom.: 371236 Cov.: 37 AF XY: 0.712 AC XY: 516985 AN XY: 725736

Gnomad4 AFR exome AF: 0.931

Gnomad4 AMR exome AF: 0.850

Gnomad4 ASJ exome AF: 0.737

Gnomad4 EAS exome AF: 0.899

Gnomad4 SAS exome AF: 0.841

Gnomad4 FIN exome AF: 0.556

Gnomad4 NFE exome AF: 0.684

Gnomad4 OTH exome AF: 0.737

GnomAD4 genome AF: 0.769 AC: 116925 AN: 152146 Hom.: 45989 Cov.: 33 AF XY: 0.766 AC XY: 56958 AN XY: 74364

Gnomad4 AFR AF: 0.922

Gnomad4 AMR AF: 0.814

Gnomad4 ASJ AF: 0.743

Gnomad4 EAS AF: 0.886

Gnomad4 SAS AF: 0.857

Gnomad4 FIN AF: 0.554

Gnomad4 NFE AF: 0.683

Gnomad4 OTH AF: 0.775

Alfa AF: 0.708 Hom.: 76835

Bravo AF: 0.793

Asia WGS AF: 0.883 AC: 3069 AN: 3476

EpiCase AF: 0.700

EpiControl AF: 0.694

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 18802358) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 97% of patients studied by a panel of primary immunodeficiencies. Number of patients: 93. Only high quality variants are reported. -

IL21-related infantile inflammatory bowel disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	8.2
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs4833837; hg19: chr4-123536963; COSMIC: COSV52647413; COSMIC: COSV52647413;