chr16-27448699-G-A

Position:

• chr16-27448699-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000337929.8(IL21R):​c.1033G>A​(p.Gly345Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,613,242 control chromosomes in the GnomAD database, including 9 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G345D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (9 hom.)
• Consequence: IL21R ENST00000337929.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 0.373

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]

IL21R-AS1 (HGNC:27551): (IL21R antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034081936).
• BP6: Variant 16-27448699-G-A is Benign according to our data. Variant chr16-27448699-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225037.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}. Variant chr16-27448699-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL21R	NM_181078.3	c.1033G>A	p.Gly345Ser	missense_variant	9/9	ENST00000337929.8	NP_851564.1
IL21R-AS1	NR_037158.1	n.1585C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL21R	ENST00000337929.8	c.1033G>A	p.Gly345Ser	missense_variant	9/9	1	NM_181078.3	ENSP00000338010	P1
IL21R-AS1	ENST00000563191.1	n.1585C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 404 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

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: 0.00426

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00231 AC: 578 AN: 250206 Hom.: 0 AF XY: 0.00244 AC XY: 331 AN XY: 135634

Gnomad AFR exome AF: 0.000807

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00400 AC: 5847 AN: 1460900 Hom.: 9 Cov.: 31 AF XY: 0.00399 AC XY: 2898 AN XY: 726760

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00376

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000133

Gnomad4 NFE exome AF: 0.00482

Gnomad4 OTH exome AF: 0.00441

GnomAD4 genome AF: 0.00265 AC: 404 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.00260 AC XY: 194 AN XY: 74498

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00426

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00402 Hom.: 2

Bravo AF: 0.00300

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00235 AC: 285

EpiCase AF: 0.00442

EpiControl AF: 0.00504

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cryptosporidiosis-chronic cholangitis-liver disease syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 22, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	IL21R: BP4 -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2014

- -

IgE responsiveness, atopic;C3554687:Cryptosporidiosis-chronic cholangitis-liver disease syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

IL21R NM_021798.3 exon 9 p.Gly345Ser (c.1033G>A): This variant has been reported in the literature in at least 1 individual referred for an unspecified immune disorder (Hagman 2017 PMID:27513193). This variant is present in 0.3% (480/128220) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-27460020-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:225037). This variant amino acid Serine (Ser) is present in 4 species (Crab-eating macaque, Squirrel monkey, Bat, Microbat); this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.0
DANN	Benign	0.70
DEOGEN2	Benign	0.10	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.48	.;.;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.40	N;N;N
REVEL	Benign	0.087
Sift	Benign	0.37	T;T;T
Sift4G	Benign	0.090	T;T;T
Polyphen		0.55	P;P;P
Vest4		0.043
MVP		0.55
MPC		0.29
ClinPred		0.0022	T
GERP RS		1.9
Varity_R		0.025
gMVP		0.31

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: rs56148525; hg19: chr16-27460020; COSMIC: COSV100559768; COSMIC: COSV100559768;