rs2228144

chr1-154429203-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000565.4(IL6R):c.93G>A(p.Ala31=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,610,256 control chromosomes in the GnomAD database, including 18,943 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1439 hom., cov: 31)
  • Exomes 𝑓: 0.15 (17504 hom.)
• Consequence: IL6R NM_000565.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.21

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-154429203-G-A is Benign according to our data. Variant chr1-154429203-G-A is described in ClinVar as [Benign]. Clinvar id is 1164401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL6R	NM_000565.4	c.93G>A	p.Ala31=	synonymous_variant	2/10	ENST00000368485.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL6R	ENST00000368485.8	c.93G>A	p.Ala31=	synonymous_variant	2/10	1	NM_000565.4	P1
IL6R	ENST00000344086.8	c.93G>A	p.Ala31=	synonymous_variant	2/9	1
IL6R	ENST00000622330.5	c.93G>A	p.Ala31=	synonymous_variant	2/7	1
IL6R	ENST00000512471.1	c.93G>A	p.Ala31=	synonymous_variant	2/4	4

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19471 AN: 151990 Hom.: 1436 Cov.: 31

Gnomad AFR AF: 0.0623

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.139 AC: 34830 AN: 250842 Hom.: 2700 AF XY: 0.141 AC XY: 19133 AN XY: 135578

Gnomad AFR exome AF: 0.0603

Gnomad AMR exome AF: 0.0767

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.113

Gnomad SAS exome AF: 0.148

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.152 AC: 222252 AN: 1458148 Hom.: 17504 Cov.: 33 AF XY: 0.152 AC XY: 110365 AN XY: 724486

Gnomad4 AFR exome AF: 0.0549

Gnomad4 AMR exome AF: 0.0799

Gnomad4 ASJ exome AF: 0.175

Gnomad4 EAS exome AF: 0.110

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.128 AC: 19480 AN: 152108 Hom.: 1439 Cov.: 31 AF XY: 0.128 AC XY: 9508 AN XY: 74358

Gnomad4 AFR AF: 0.0621

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.193

Gnomad4 EAS AF: 0.107

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.163

Gnomad4 OTH AF: 0.132

Alfa AF: 0.152 Hom.: 1919

Bravo AF: 0.120

Asia WGS AF: 0.157 AC: 545 AN: 3478

EpiCase AF: 0.164

EpiControl AF: 0.160

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IL6R-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.6
Dann	Benign	0.41

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: rs2228144; hg19: chr1-154401679; COSMIC: COSV59816615; COSMIC: COSV59816615;