4-122612884-T-C

Variant names:

• chr4-122612884-T-C
• rs200274184
• NM_021803.4:c.405A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_021803.4(IL21):​c.405A>G​(p.Glu135Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IL21 NM_021803.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP7: Synonymous conserved (PhyloP=1.26 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL21	NM_021803.4	c.405A>G	p.Glu135Glu	synonymous_variant	Exon 4 of 5	ENST00000648588.1	NP_068575.1
IL21	NM_001207006.3	c.405A>G	p.Glu135Glu	synonymous_variant	Exon 4 of 4		NP_001193935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL21	ENST00000648588.1	c.405A>G	p.Glu135Glu	synonymous_variant	Exon 4 of 5		NM_021803.4	ENSP00000497915.1
IL21	ENST00000611104.2	c.405A>G	p.Glu135Glu	synonymous_variant	Exon 4 of 4	1		ENSP00000477555.1
IL21	ENST00000647784.1	n.257A>G		non_coding_transcript_exon_variant	Exon 3 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460190 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726476

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111172

Other (OTH) AF: 0.00 AC: 0 AN: 60334

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.0
DANN	Benign	0.69
PhyloP100		1.3

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

Other links and lift over

dbSNP: rs200274184; hg19: chr4-123534039;