4-122612735-C-T

Variant names:

• chr4-122612735-C-T
• NM_021803.4:c.464G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021803.4(IL21):​c.464G>A​(p.Arg155Lys) 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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: 1.64

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16208917).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL21	NM_021803.4	c.464G>A	p.Arg155Lys	missense_variant	Exon 5 of 5	ENST00000648588.1	NP_068575.1
IL21	NM_001207006.3	c.*92G>A		3_prime_UTR_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.464G>A	p.Arg155Lys	missense_variant	Exon 5 of 5		NM_021803.4	ENSP00000497915.1
IL21	ENST00000611104	c.*92G>A		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000477555.1
IL21	ENST00000647784.1	n.316G>A		non_coding_transcript_exon_variant	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 155 of the IL21 protein (p.Arg155Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IL21-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Uncertain	0.98
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.35	.;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.15	.;N
REVEL	Benign	0.091
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Vest4		0.34
MVP		0.15
MPC		0.69
ClinPred		0.54	D
GERP RS		3.9
gMVP		0.15

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-123533890; COSMIC: COSV52646223;