1-154405634-TGGCCGTC-T

Variant names:

• chr1-154405634-TGGCCGTC-T
• rs1687658446
• NM_000565.4:c.9_15delCGTCGGC

Variant summary

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

The NM_000565.4(IL6R):​c.9_15delCGTCGGC​(p.Val4AlafsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,380,502 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IL6R NM_000565.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36
• 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-AS1 (HGNC:53716): (IL6R antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.9_15delCGTCGGC	p.Val4AlafsTer30	frameshift	Exon 1 of 10	NP_000556.1	P08887-1
	IL6R	NM_001382769.1		c.9_15delCGTCGGC	p.Val4AlafsTer30	frameshift	Exon 1 of 11	NP_001369698.1
	IL6R	NM_001382770.1		c.9_15delCGTCGGC	p.Val4AlafsTer30	frameshift	Exon 1 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.9_15delCGTCGGC	p.Val4AlafsTer30	frameshift	Exon 1 of 10	ENSP00000357470.3	P08887-1
	IL6R	ENST00000344086.8	TSL:1	c.9_15delCGTCGGC	p.Val4AlafsTer30	frameshift	Exon 1 of 9	ENSP00000340589.4	P08887-2
	IL6R	ENST00000622330.5	TSL:1	c.9_15delCGTCGGC	p.Val4AlafsTer30	frameshift	Exon 1 of 7	ENSP00000477739.1	A0A087WTB5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1380502 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 681910

African (AFR) AF: 0.00 AC: 0 AN: 30606

American (AMR) AF: 0.00 AC: 0 AN: 36158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24868

East Asian (EAS) AF: 0.00 AC: 0 AN: 35218

South Asian (SAS) AF: 0.00 AC: 0 AN: 79284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4302

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078860

Other (OTH) AF: 0.00 AC: 0 AN: 57528

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1687658446; hg19: chr1-154378110;