16-27430090-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_181078.3(IL21R):c.19G>A(p.Ala7Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,605,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A7G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: IL21R NM_181078.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.115

Genes affected

IL21R (HGNC:6006): (interleukin 21 receptor) The protein encoded by this gene is a cytokine receptor for interleukin 21 (IL21). It belongs to the type I cytokine receptors, and has been shown to form a heterodimeric receptor complex with the common gamma-chain, a receptor subunit also shared by the receptors for interleukin 2, 4, 7, 9, and 15. This receptor transduces the growth promoting signal of IL21, and is important for the proliferation and differentiation of T cells, B cells, and natural killer (NK) cells. The ligand binding of this receptor leads to the activation of multiple downstream signaling molecules, including JAK1, JAK3, STAT1, and STAT3. Knockout studies of a similar gene in mouse suggest a role for this gene in regulating immunoglobulin production. Three alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.004985571).
• BP6: Variant 16-27430090-G-A is Benign according to our data. Variant chr16-27430090-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 540994.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-27430090-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL21R	NM_181078.3	c.19G>A	p.Ala7Thr	missense_variant	2/9	ENST00000337929.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL21R	ENST00000337929.8	c.19G>A	p.Ala7Thr	missense_variant	2/9	1	NM_181078.3	P1
IL21R	ENST00000395754.4	c.19G>A	p.Ala7Thr	missense_variant	2/9	1		P1
IL21R	ENST00000564089.5	c.19G>A	p.Ala7Thr	missense_variant	3/10	5		P1
IL21R	ENST00000697146.1	c.19G>A	p.Ala7Thr	missense_variant, NMD_transcript_variant	1/7

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000196 AC: 47 AN: 239286 Hom.: 0 AF XY: 0.000130 AC XY: 17 AN XY: 130862

Gnomad AFR exome AF: 0.00259

Gnomad AMR exome AF: 0.0000875

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000365

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000557 AC: 81 AN: 1453076 Hom.: 0 Cov.: 31 AF XY: 0.0000594 AC XY: 43 AN XY: 723298

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74486

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.000555

ESP6500AA AF: 0.00296 AC: 13

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000289 AC: 35

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cryptosporidiosis-chronic cholangitis-liver disease syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	3.4
Dann	Uncertain	0.98
DEOGEN2	Benign	0.13	T;T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.025	N
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0050	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.69	N;N;N
REVEL	Benign	0.021
Sift	Benign	0.096	T;T;T
Sift4G	Uncertain	0.026	D;D;D
Polyphen		0.053	B;B;B
Vest4		0.15
MVP		0.59
MPC		0.27
ClinPred		0.0049	T
GERP RS		0.70
Varity_R		0.033
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs145338579; hg19: chr16-27441411;