NM_021803.4:c.234C>T

Variant names:

• chr4-122615808-G-A
• rs4833837
• NM_021803.4:c.234C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021803.4(IL21):​c.234C>T​(p.Cys78Cys) 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:6 O:1
• Conservation: PhyloP100: 0.583
• Publications: 47 publications found

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]

IL21 Gene-Disease associations (from GenCC):

• IL21-related infantile inflammatory bowel disease

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• common variable immunodeficiency

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021803.4. 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
	IL21	NM_021803.4	MANE Select	c.234C>T	p.Cys78Cys	synonymous	Exon 3 of 5	NP_068575.1	Q9HBE4-1
	IL21	NM_001207006.3		c.234C>T	p.Cys78Cys	synonymous	Exon 3 of 4	NP_001193935.1	Q9HBE4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL21	ENST00000648588.1	MANE Select	c.234C>T	p.Cys78Cys	synonymous	Exon 3 of 5	ENSP00000497915.1	Q9HBE4-1
	IL21	ENST00000611104.2	TSL:1	c.234C>T	p.Cys78Cys	synonymous	Exon 3 of 4	ENSP00000477555.1	Q9HBE4-2
	IL21	ENST00000647784.1		n.86C>T		non_coding_transcript_exon	Exon 2 of 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

GnomAD2 exomes AF: 0.744 AC: 186361 AN: 250468 AF XY: 0.741

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 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

African (AFR) AF: 0.931 AC: 31116 AN: 33418

American (AMR) AF: 0.850 AC: 37966 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 19233 AN: 26104

East Asian (EAS) AF: 0.899 AC: 35653 AN: 39664

South Asian (SAS) AF: 0.841 AC: 72352 AN: 86054

European-Finnish (FIN) AF: 0.556 AC: 29649 AN: 53346

Middle Eastern (MID) AF: 0.826 AC: 4503 AN: 5452

European-Non Finnish (NFE) AF: 0.684 AC: 759021 AN: 1109534

Other (OTH) AF: 0.737 AC: 44416 AN: 60258

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

African (AFR) AF: 0.922 AC: 38296 AN: 41556

American (AMR) AF: 0.814 AC: 12439 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 2579 AN: 3472

East Asian (EAS) AF: 0.886 AC: 4596 AN: 5186

South Asian (SAS) AF: 0.857 AC: 4128 AN: 4818

European-Finnish (FIN) AF: 0.554 AC: 5845 AN: 10542

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.683 AC: 46424 AN: 67966

Other (OTH) AF: 0.775 AC: 1636 AN: 2110

Alfa AF: 0.720 Hom.: 124183

Bravo AF: 0.793

Asia WGS AF: 0.883 AC: 3069 AN: 3476

EpiCase AF: 0.700

EpiControl AF: 0.694

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	2	not specified (2)
-	-	1	IL21-related infantile inflammatory bowel disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.2
DANN	Benign	0.75
PhyloP100		0.58
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4833837; hg19: chr4-123536963; COSMIC: COSV52647413; COSMIC: COSV52647413;