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rs2228145

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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D358Y) has been classified 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

17

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O: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]

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 UniProt
IL6RNM_000565.4 linkuse as main transcriptc.1073A>C p.Asp358Ala missense_variant 9/10 ENST00000368485.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IL6RENST00000368485.8 linkuse as main transcriptc.1073A>C p.Asp358Ala missense_variant 9/101 NM_000565.4 P1P08887-1

Frequencies

GnomAD3 genomes
AF:
0.321
AC:
48587
AN:
151302
Hom.:
9020
Cov.:
30
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.:
30
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.:
30
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:3Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingUnidad de Genómica Garrahan, Hospital de Pediatría GarrahanJan 24, 2024This 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 condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 17, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Interleukin 6, serum level of, quantitative trait locus Other:1
association, no assertion criteria providedliterature onlyOMIMApr 01, 2007- -
Soluble interleukin-6 receptor, serum level of, quantitative trait locus Other:1
association, no assertion criteria providedliterature onlyOMIMApr 01, 2007- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.51
Cadd
Benign
15
Dann
Benign
0.92
DEOGEN2
Benign
0.34
T
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.36
FATHMM_MKL
Benign
0.42
N
LIST_S2
Benign
0.48
T
MetaRNN
Benign
0.00012
T
MetaSVM
Benign
-0.98
T
MutationTaster
Benign
1.0
P;P
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-1.9
N
REVEL
Benign
0.091
Sift
Benign
0.24
T
Sift4G
Benign
0.34
T
Polyphen
0.12
B
Vest4
0.29
MPC
0.33
ClinPred
0.0088
T
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.

Other links and lift over

dbSNP: rs2228145; hg19: chr1-154426970; COSMIC: COSV59816312; COSMIC: COSV59816312; API