4-122620894-G-C

Variant names:

• chr4-122620894-G-C
• rs1158040184
• NM_021803.4:c.118C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021803.4(IL21):​c.118C>G​(p.Arg40Gly) 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 benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IL21 NM_021803.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58
• 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-AS1 (HGNC:40299): (IL21 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22368905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL21	NM_021803.4	c.118C>G	p.Arg40Gly	missense_variant	Exon 1 of 5	ENST00000648588.1	NP_068575.1
IL21	NM_001207006.3	c.118C>G	p.Arg40Gly	missense_variant	Exon 1 of 4		NP_001193935.1
IL21-AS1	NR_104126.1	n.735G>C		non_coding_transcript_exon_variant	Exon 3 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL21	ENST00000648588.1	c.118C>G	p.Arg40Gly	missense_variant	Exon 1 of 5		NM_021803.4	ENSP00000497915.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1052639). This variant has not been reported in the literature in individuals affected with IL21-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 40 of the IL21 protein (p.Arg40Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	0.064
Eigen_PC	Benign	0.074
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.73	.;T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.96	T
PhyloP100		1.6
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-4.4	.;D;.
REVEL	Benign	0.088
Sift	Uncertain	0.0070	.;D;.
Sift4G	Uncertain	0.015	.;D;D
Vest4		0.37, 0.38
MVP		0.38
MPC		1.3
ClinPred		0.97	D
GERP RS		1.3
PromoterAI		-0.040	Neutral
gMVP		0.61
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1158040184; hg19: chr4-123542049;