chr1-154429203-G-A

Variant names:

• chr1-154429203-G-A
• rs2228144
• NM_000565.4:c.93G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000565.4(IL6R):​c.93G>A​(p.Ala31Ala) 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:3
• Conservation: PhyloP100: -2.21
• Publications: 35 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
IL6R	NM_000565.4	c.93G>A	p.Ala31Ala	synonymous_variant	Exon 2 of 10	ENST00000368485.8	NP_000556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL6R	ENST00000368485.8	c.93G>A	p.Ala31Ala	synonymous_variant	Exon 2 of 10	1	NM_000565.4	ENSP00000357470.3

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

GnomAD2 exomes AF: 0.139 AC: 34830 AN: 250842 AF XY: 0.141

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 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

African (AFR) AF: 0.0549 AC: 1834 AN: 33412

American (AMR) AF: 0.0799 AC: 3566 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 4563 AN: 26098

East Asian (EAS) AF: 0.110 AC: 4338 AN: 39552

South Asian (SAS) AF: 0.144 AC: 12421 AN: 86188

European-Finnish (FIN) AF: 0.165 AC: 8790 AN: 53364

Middle Eastern (MID) AF: 0.166 AC: 955 AN: 5752

European-Non Finnish (NFE) AF: 0.159 AC: 176745 AN: 1108918

Other (OTH) AF: 0.150 AC: 9040 AN: 60208

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

African (AFR) AF: 0.0621 AC: 2577 AN: 41506

American (AMR) AF: 0.107 AC: 1642 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 669 AN: 3470

East Asian (EAS) AF: 0.107 AC: 554 AN: 5176

South Asian (SAS) AF: 0.163 AC: 785 AN: 4820

European-Finnish (FIN) AF: 0.159 AC: 1676 AN: 10568

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.163 AC: 11081 AN: 67974

Other (OTH) AF: 0.132 AC: 277 AN: 2104

Alfa AF: 0.142 Hom.: 2382

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

IL6R-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.41
PhyloP100		-2.2
PromoterAI		-0.024	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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