1-154429233-C-A

Variant names:

• chr1-154429233-C-A
• rs1393806703
• NM_000565.4:c.123C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000565.4(IL6R):​c.123C>A​(p.Asp41Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IL6R NM_000565.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.655
• Publications: 0 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08331776).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000565.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6R	NM_000565.4	MANE Select	c.123C>A	p.Asp41Glu	missense	Exon 2 of 10	NP_000556.1	P08887-1
	IL6R	NM_001382769.1		c.123C>A	p.Asp41Glu	missense	Exon 2 of 11	NP_001369698.1
	IL6R	NM_001382770.1		c.123C>A	p.Asp41Glu	missense	Exon 2 of 11	NP_001369699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6R	ENST00000368485.8	TSL:1 MANE Select	c.123C>A	p.Asp41Glu	missense	Exon 2 of 10	ENSP00000357470.3	P08887-1
	IL6R	ENST00000344086.8	TSL:1	c.123C>A	p.Asp41Glu	missense	Exon 2 of 9	ENSP00000340589.4	P08887-2
	IL6R	ENST00000622330.5	TSL:1	c.123C>A	p.Asp41Glu	missense	Exon 2 of 7	ENSP00000477739.1	A0A087WTB5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461606 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727050

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111768

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.53	N
PhyloP100		0.66
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.44	N
REVEL	Benign	0.012
Sift	Benign	0.10	T
Sift4G	Benign	0.26	T
Polyphen		0.010	B
Vest4		0.11
MutPred		0.33		Gain of disorder (P = 0.1076)
MVP		0.43
MPC		0.23
ClinPred		0.18	T
GERP RS		3.0
PromoterAI		-0.033	Neutral
Varity_R		0.12
gMVP		0.65
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1393806703; hg19: chr1-154401709;