chr1-154454494-A-C

Variant names:

• chr1-154454494-A-C
• rs2228145
• NM_000565.4:c.1073A>C
• IL6R p.Asp358Ala

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACGS-UK Somatic Oncogenicity v2025). O4_SupportingB1_StrongB3_Supporting

The NM_000565.4(IL6R):c.1073A>C (p.Asp358Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene IL6R is a tumor suppressor gene (CancerMine: 1 TSG, 1 oncogene citations). The gene IL6R is a known oncogene (CancerMine: 1 TSG, 1 oncogene citations). 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) The variant has been observed in cBioPortal in 10 samples across 5 studies and 5 cancer types; somatic enrichment level: SUPPORTING (Observed repeatedly in cBioPortal somatic datasets.). 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:2
• Conservation: PhyloP100: 0.519
• Publications: 685 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: ClinGen, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 1.0) — Supporting (O4); cBioPortal: samples=10 | studies=5 | cancer types=5 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.538 — exceeds 1% threshold (B1 applied)
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

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

Sel.	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	Prot: NP_000556.1 UniProt:
	IL6R NM_001382769.1		c.1172A>C p.Asp391Ala	missense	Exon 10 of 11	Prot: NP_001369698.1
	IL6R NM_001382770.1		c.1166A>C p.Asp389Ala	missense	Exon 10 of 11	Prot: NP_001369699.1

IL6R NM_000565.4

MANE Select

HGVSc / HGVSpc.1073A>Cp.Asp358Ala

Exon rankExon 9 of 10

missense

Prot: NP_000556.1UniProt: A0N0L5P08887-1

IL6R NM_001382769.1

HGVSc / HGVSpc.1172A>Cp.Asp391Ala

Exon rankExon 10 of 11

missense

Prot: NP_001369698.1

IL6R NM_001382770.1

HGVSc / HGVSpc.1166A>Cp.Asp389Ala

Exon rankExon 10 of 11

missense

Prot: NP_001369699.1

Ensembl Transcripts

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

IL6R ENST00000368485.8

TSL:1MANE Select

HGVSc / HGVSpc.1073A>Cp.Asp358Ala

Exon rankExon 9 of 10

missense

Prot: ENSP00000357470.3UniProt: P08887-1

IL6R ENST00000344086.8

TSL:1

HGVSc / HGVSpc.1066+4514A>C

Exon rankIntron 8 of 8

intron

Prot: ENSP00000340589.4UniProt: P08887-2

IL6R ENST00000858510.1

HGVSc / HGVSpc.1265A>Cp.Asp422Ala

Exon rankExon 11 of 12

missense

Prot: ENSP00000528569.1UniProt: A0ACI8RD36

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.321	AC:48587	Hom:9020	AN:151302	Cov:30
GnomAD2 exomes	AF: 0.379	AC:94659	Hom:	AN:249648	Cov:
GnomAD4 exome	AF: 0.390	AC:565992	Hom:113611	AN:1453118	Cov:30
GnomAD4 genome	AF: 0.321	AC:48588	Hom:9020	AN:151420	Cov:30
TOPMed (Bravo)	AF: 0.335	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.368	AC:161434	Hom:31730	AN:438752	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.373	AC:873	Hom:180	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.390	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.327	AC:98	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.317	AC:4121	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.286	AC:998	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.424	AC:3070	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.362	AC:721	Hom:	AN:1994	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.386	AC:47221	Hom:9152	AN:122374	Cov:
Turkish Variome	AF: 0.370	AC:2465	Hom:486	AN:6660	Cov:
UK10K	AF: 0.424	AC:3210	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.365	AC:3267	Hom:612	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.396 *	4380	11058	0.403 *	6967	17306
BipEx(Bipolar disorder (including schizoaffective))	0.402	11429	28420	0.400	11532	28838
Epi25(Epilepsy)	0.368	15428	41958	0.382	25525	66876
SCHEMA(Schizophrenia)	0.373	58117	155846	0.389	101899	262086

Showing 4 cohortsAllele 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

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	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

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	15
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
FuncVEP CTI	Benign	0.00039
GPN-Star LLR	N/A	-3.7
GPN-Star score	N/A	3.7
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.00012	T
MetaSVM	Benign	-0.98	T
Mutation Taster	N/A	95/5	polymorphism (auto)
PhyloP100	Benign	0.52
popEVE	Benign	-3.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Benign	0.091
Sift	Benign	0.24	T
Sift4G	Benign	0.34	T
Varity_R	N/A	0.20
VESM-3B	Benign	-6.6

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.070
SpliceAI score (max)	Benign	0.11	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2228145;

hg19: chr1-154426970;

COSMIC: COSV59816312;

COSMIC: COSV59816312;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar