rs2228145

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000565.4(IL6R):c.1073A>C(p.Asp358Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,604,538 control chromosomes in the GnomAD database, including 122,631 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 9020 hom., cov: 30)

Exomes 𝑓: 0.39 ( 113611 hom. )

Consequence

IL6R
NM_000565.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:2

Conservation

PhyloP100: 0.519

Variant links:

Genes affected

IL6R (HGNC:6019): (interleukin 6 receptor) This gene encodes a subunit of the interleukin 6 (IL6) receptor complex. Interleukin 6 is a potent pleiotropic cytokine that regulates cell growth and differentiation and plays an important role in the immune response. The IL6 receptor is a protein complex consisting of this protein and interleukin 6 signal transducer (IL6ST/GP130/IL6-beta), a receptor subunit also shared by many other cytokines. Dysregulated production of IL6 and this receptor are implicated in the pathogenesis of many diseases, such as multiple myeloma, autoimmune diseases and prostate cancer. Alternatively spliced transcript variants encoding distinct isoforms have been identified in this gene. A pseudogene of this gene is found on chromosome 9. [provided by RefSeq, Aug 2020]

IL6R links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2167276E-4).

BP6

Variant 1-154454494-A-C is Benign according to our data. Variant chr1-154454494-A-C is described in ClinVar as [Benign]. Clinvar id is 14660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL6R	NM_000565.4 linkuse as main transcript	c.1073A>C	p.Asp358Ala	missense_variant	9/10	ENST00000368485.8	NP_000556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL6R	ENST00000368485.8 linkuse as main transcript	c.1073A>C	p.Asp358Ala	missense_variant	9/10	1	NM_000565.4	ENSP00000357470	P1	P08887-1

Frequencies

GnomAD3 genomes

AF:

0.321

AC:

48587

AN:

151302

Hom.:

9020

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.471

Gnomad AMR

AF:

0.489

Gnomad ASJ

AF:

0.411

Gnomad EAS

AF:

0.361

Gnomad SAS

AF:

0.291

Gnomad FIN

AF:

0.280

Gnomad MID

AF:

0.367

Gnomad NFE

AF:

0.394

Gnomad OTH

AF:

0.346

GnomAD3 exomes

AF:

0.379

AC:

94659

AN:

249648

Hom.:

19150

AF XY:

0.376

AC XY:

50669

AN XY:

134926

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.550

Gnomad ASJ exome

AF:

0.412

Gnomad EAS exome

AF:

0.381

Gnomad SAS exome

AF:

0.307

Gnomad FIN exome

AF:

0.289

Gnomad NFE exome

AF:

0.396

Gnomad OTH exome

AF:

0.388

GnomAD4 exome

AF:

0.390

AC:

565992

AN:

1453118

Hom.:

113611

Cov.:

AF XY:

0.387

AC XY:

279734

AN XY:

723282

show subpopulations

Gnomad4 AFR exome

AF:

0.125

Gnomad4 AMR exome

AF:

0.544

Gnomad4 ASJ exome

AF:

0.415

Gnomad4 EAS exome

AF:

0.392

Gnomad4 SAS exome

AF:

0.307

Gnomad4 FIN exome

AF:

0.293

Gnomad4 NFE exome

AF:

0.403

Gnomad4 OTH exome

AF:

0.369

GnomAD4 genome

AF:

0.321

AC:

48588

AN:

151420

Hom.:

9020

Cov.:

AF XY:

0.317

AC XY:

23400

AN XY:

73922

show subpopulations

Gnomad4 AFR

AF:

0.135

Gnomad4 AMR

AF:

0.489

Gnomad4 ASJ

AF:

0.411

Gnomad4 EAS

AF:

0.361

Gnomad4 SAS

AF:

0.290

Gnomad4 FIN

AF:

0.280

Gnomad4 NFE

AF:

0.394

Gnomad4 OTH

AF:

0.343

Alfa

AF:

0.388

Hom.:

19659

Bravo

AF:

0.335

TwinsUK

AF:

0.424

AC:

1571

ALSPAC

AF:

0.425

AC:

1639

ESP6500AA

AF:

0.145

AC:

641

ESP6500EA

AF:

0.405

AC:

3480

ExAC

AF:

0.369

AC:

44828

Asia WGS

AF:

0.286

AC:

998

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 82% of patients studied by a panel of primary immunodeficiencies. Number of patients: 72. Only high quality variants are reported. -

IL6R-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Interleukin 6, serum level of, quantitative trait locus

Other:1

association, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

Soluble interleukin-6 receptor, serum level of, quantitative trait locus

Other:1

association, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.34

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.48

MetaRNN

Benign

0.00012

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.9

REVEL

Benign

0.091

Sift

Benign

0.24

Sift4G

Benign

0.34

Polyphen

0.12

Vest4

0.29

MPC

0.33

ClinPred

0.0088

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over