rs2228145

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6_Strong

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 cumulative frequency of 0.383 (AC=614,580) in the gnomAD database across 1,604,538 control chromosomes, including 122,631 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.538. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.D358V: unknown significance (ClinVar VariationId 4523836); p.D358Y: Uncertain_significance (ClinVar VariationId 1362683, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

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/Likely benign criteria provided, multiple submitters, no conflicts B:6O:2

Conservation

PhyloP100: 0.519

Publications

631 publications found

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 Gene-Disease associations (from GenCC):

hyper-IgE recurrent infection syndrome 5, autosomal recessive
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

IL6R links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000565.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -14 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.5381 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000565.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL6R	NM_000565.4	MANE Select	c.1073A>C	p.Asp358Ala	missense	Exon 9 of 10	NP_000556.1	A0N0L5
IL6R	NM_001382769.1		c.1172A>C	p.Asp391Ala	missense	Exon 10 of 11	NP_001369698.1
IL6R	NM_001382770.1		c.1166A>C	p.Asp389Ala	missense	Exon 10 of 11	NP_001369699.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL6R	ENST00000368485.8	TSL:1 MANE Select	c.1073A>C	p.Asp358Ala	missense	Exon 9 of 10	ENSP00000357470.3	P08887-1
IL6R	ENST00000344086.8	TSL:1	c.1066+4514A>C		intron	N/A	ENSP00000340589.4	P08887-2
IL6R	ENST00000858510.1		c.1265A>C	p.Asp422Ala	missense	Exon 11 of 12	ENSP00000528569.1	A0ACI8RD36

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

GnomAD2 exomes

AF:

0.379

AC:

94659

AN:

249648

AF XY:

0.376

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 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

African (AFR)

AF:

0.125

AC:

4182

AN:

33406

American (AMR)

AF:

0.544

AC:

24232

AN:

44556

Ashkenazi Jewish (ASJ)

AF:

0.415

AC:

10817

AN:

26078

East Asian (EAS)

AF:

0.392

AC:

15549

AN:

39640

South Asian (SAS)

AF:

0.307

AC:

26438

AN:

86012

European-Finnish (FIN)

AF:

0.293

AC:

15606

AN:

53224

Middle Eastern (MID)

AF:

0.365

AC:

2101

AN:

5752

European-Non Finnish (NFE)

AF:

0.403

AC:

444872

AN:

1104308

Other (OTH)

AF:

0.369

AC:

22195

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

15809

31618

47427

63236

79045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13778

27556

41334

55112

68890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.321

AC:

48588

AN:

151420

Hom.:

9020

Cov.:

AF XY:

0.317

AC XY:

23400

AN XY:

73922

show subpopulations

African (AFR)

AF:

0.135

AC:

5578

AN:

41212

American (AMR)

AF:

0.489

AC:

7425

AN:

15182

Ashkenazi Jewish (ASJ)

AF:

0.411

AC:

1426

AN:

3466

East Asian (EAS)

AF:

0.361

AC:

1850

AN:

5118

South Asian (SAS)

AF:

0.290

AC:

1390

AN:

4792

European-Finnish (FIN)

AF:

0.280

AC:

2926

AN:

10464

Middle Eastern (MID)

AF:

0.381

AC:

112

AN:

294

European-Non Finnish (NFE)

AF:

0.394

AC:

26730

AN:

67876

Other (OTH)

AF:

0.343

AC:

723

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1566

3131

4697

6262

7828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

470

940

1410

1880

2350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.335

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.368

AC:

161434

AN:

438752

Hom.:

31730

Local populations

ABraOM SABE-WGS-1171

AF:

0.373

AC:

873

AN:

2342

Hom.:

180

ChinaMAP Phase 1

AF:

0.390

Denmark Genome

AF:

0.327

AC:

AN:

300

ESP6500 (Exome Variant Server)

AF:

0.317

AC:

4121

AN:

13006

show subpopulations

European American

AF:

0.405

AC:

3480

AN:

8600

African American

AF:

0.145

AC:

641

AN:

4406

GenomeAsia100K

AF:

0.286

AC:

998

AN:

3478

show subpopulations

Oceania

AF:

0.135

AC:

AN:

148

Hom.:

North-East Asia

AF:

0.474

AC:

333

AN:

702

Hom.:

South-East Asia

AF:

0.212

AC:

147

AN:

692

Hom.:

South Asia

AF:

0.245

AC:

355

AN:

1448

Hom.:

Africa

AF:

0.0865

AC:

AN:

208

Hom.:

America

AF:

0.635

AC:

AN:

Hom.:

West Eurasia

AF:

0.404

AC:

AN:

228

Hom.:

Korea4K (4,157 Koreans)

AF:

0.424

AC:

3070

AN:

7234

Qatari Genome

AF:

0.362

AC:

721

AN:

1994

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.386

AC:

47221

AN:

122374

Hom.:

9152

Turkish Variome

AF:

0.370

AC:

2465

AN:

6660

Hom.:

486

UK10K

AF:

0.424

AC:

3210

AN:

7562

show subpopulations

TwinsUK

AF:

0.425

AC:

1518

AN:

3574

ALSPAC

AF:

0.425

AC:

1639

AN:

3854

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.365

AC:

3267

AN:

8960

Hom.:

612

Case/control cohorts

Cohort

Cases

Controls

ASC

(Autism)

4380 / 11058AF: 0.396093

6967 / 17306AF: 0.402577

BipEx

(Bipolar disorder (including schizoaffective))

11429 / 28420AF: 0.402146

11532 / 28838AF: 0.399889

Epi25

(Epilepsy)

15428 / 41958AF: 0.367701

25525 / 66876AF: 0.381677

SCHEMA

(Schizophrenia)

58117 / 155846AF: 0.372913

101899 / 262086AF: 0.388800

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

IL6R-related disorder (1)

Interleukin 6, serum level of, quantitative trait locus (1)

Soluble interleukin-6 receptor, serum level of, quantitative trait locus (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

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

PhyloP100

0.52

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.9

REVEL

Benign

0.091

Sift

Benign

0.24

Sift4G

Benign

0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

popEVE

Benign

-3.0

(source)

VESM-3B

Benign

-6.6

(source)

FuncVEP CTI

Benign

0.00039

(source)

AlphaGenome AVI

Uncertain

(source)

GPN-Star LLR

-3.7

(source)

GPN-Star score

3.7

(source)

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Pangolin (max)

Benign

0.070

(source)

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over