NM_000565.4:c.996+131T>C

Variant names:

• chr1-154448302-T-C
• rs7529229
• NM_000565.4:c.996+131T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000565.4(IL6R):​c.996+131T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 708,300 control chromosomes in the GnomAD database, including 65,063 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.47 (18131 hom., cov: 32)
  • Exomes 𝑓: 0.40 (46932 hom.)
• Consequence: IL6R NM_000565.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0800
• Publications: 77 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6R	NM_000565.4	MANE Select	c.996+131T>C		intron	N/A	NP_000556.1
	IL6R	NM_001382769.1		c.996+131T>C		intron	N/A	NP_001369698.1
	IL6R	NM_001382770.1		c.1089+131T>C		intron	N/A	NP_001369699.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6R	ENST00000368485.8	TSL:1 MANE Select	c.996+131T>C		intron	N/A	ENSP00000357470.3
	IL6R	ENST00000344086.8	TSL:1	c.996+131T>C		intron	N/A	ENSP00000340589.4
	IL6R	ENST00000476006.5	TSL:3	c.810+131T>C		intron	N/A	ENSP00000423668.1

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71759 AN: 151930 Hom.: 18086 Cov.: 32

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.549

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.457

GnomAD4 exome AF: 0.403 AC: 224080 AN: 556252 Hom.: 46932 AF XY: 0.396 AC XY: 117042 AN XY: 295712

African (AFR) AF: 0.651 AC: 10147 AN: 15582

American (AMR) AF: 0.574 AC: 16794 AN: 29236

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 6881 AN: 16242

East Asian (EAS) AF: 0.394 AC: 13605 AN: 34506

South Asian (SAS) AF: 0.309 AC: 17657 AN: 57118

European-Finnish (FIN) AF: 0.305 AC: 14936 AN: 48912

Middle Eastern (MID) AF: 0.397 AC: 862 AN: 2172

European-Non Finnish (NFE) AF: 0.406 AC: 131086 AN: 322912

Other (OTH) AF: 0.410 AC: 12112 AN: 29572

GnomAD4 genome AF: 0.473 AC: 71853 AN: 152048 Hom.: 18131 Cov.: 32 AF XY: 0.463 AC XY: 34415 AN XY: 74318

African (AFR) AF: 0.643 AC: 26640 AN: 41458

American (AMR) AF: 0.549 AC: 8394 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1451 AN: 3470

East Asian (EAS) AF: 0.360 AC: 1861 AN: 5166

South Asian (SAS) AF: 0.294 AC: 1417 AN: 4824

European-Finnish (FIN) AF: 0.291 AC: 3078 AN: 10568

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.405 AC: 27497 AN: 67954

Other (OTH) AF: 0.453 AC: 957 AN: 2114

Alfa AF: 0.479 Hom.: 7006

Bravo AF: 0.506

Asia WGS AF: 0.323 AC: 1126 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.41
PhyloP100		0.080
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: rs7529229; hg19: chr1-154420778;