rs2228145

chr1-154454494-A-Cchr1-154454494-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:2
• Conservation: PhyloP100: 0.519

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]

ACMG classification

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
IL6R	NM_000565.4	c.1073A>C	p.Asp358Ala	missense_variant	9/10	ENST00000368485.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL6R	ENST00000368485.8	c.1073A>C	p.Asp358Ala	missense_variant	9/10	1	NM_000565.4	P1

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48587 AN: 151302 Hom.: 9020 Cov.: 30

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

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

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

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:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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, criteria provided, single submitter

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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	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

Other links and lift over

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