4-122615808-G-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021803.4(IL21):​c.234C>G​(p.Cys78Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C78C) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IL21 NM_021803.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL21	NM_021803.4	MANE Select	c.234C>G	p.Cys78Trp	missense	Exon 3 of 5	NP_068575.1
	IL21	NM_001207006.3		c.234C>G	p.Cys78Trp	missense	Exon 3 of 4	NP_001193935.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL21	ENST00000648588.1	MANE Select	c.234C>G	p.Cys78Trp	missense	Exon 3 of 5	ENSP00000497915.1
	IL21	ENST00000611104.2	TSL:1	c.234C>G	p.Cys78Trp	missense	Exon 3 of 4	ENSP00000477555.1
	IL21	ENST00000647784.1		n.86C>G		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.42	T
PhyloP100		0.58
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.90
MVP		0.75
MPC		1.9
ClinPred		0.99	D
GERP RS		5.1
gMVP		0.94
Mutation Taster		=26/74	disease causing

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: rs4833837; hg19: chr4-123536963;