rs6694817

Variant names:

• chr1-154429496-T-C
• rs6694817
• NM_000565.4:c.334+52T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-154429496-T-C
• chr1-154429496-T-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000565.4(IL6R):​c.334+52T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 1,565,550 control chromosomes in the GnomAD database, including 257,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.60 (27416 hom., cov: 32)
  • Exomes 𝑓: 0.57 (230373 hom.)
• Consequence: IL6R NM_000565.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.362
• Publications: 41 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-154429496-T-C is Benign according to our data. Variant chr1-154429496-T-C is described in ClinVar as Benign. ClinVar VariationId is 2688500.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6R	NM_000565.4	c.334+52T>C		intron_variant	Intron 2 of 9	ENST00000368485.8	NP_000556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL6R	ENST00000368485.8	c.334+52T>C		intron_variant	Intron 2 of 9	1	NM_000565.4	ENSP00000357470.3

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90395 AN: 151932 Hom.: 27369 Cov.: 32

Gnomad AFR AF: 0.679

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.655

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.567

Gnomad NFE AF: 0.570

Gnomad OTH AF: 0.582

GnomAD2 exomes AF: 0.568 AC: 126354 AN: 222604 AF XY: 0.557

Gnomad AFR exome AF: 0.684

Gnomad AMR exome AF: 0.658

Gnomad ASJ exome AF: 0.565

Gnomad EAS exome AF: 0.512

Gnomad FIN exome AF: 0.470

Gnomad NFE exome AF: 0.574

Gnomad OTH exome AF: 0.568

GnomAD4 exome AF: 0.569 AC: 803967 AN: 1413500 Hom.: 230373 Cov.: 29 AF XY: 0.564 AC XY: 392594 AN XY: 695966

African (AFR) AF: 0.682 AC: 22373 AN: 32802

American (AMR) AF: 0.658 AC: 28114 AN: 42722

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 13473 AN: 23664

East Asian (EAS) AF: 0.514 AC: 20023 AN: 38948

South Asian (SAS) AF: 0.462 AC: 37030 AN: 80220

European-Finnish (FIN) AF: 0.476 AC: 24048 AN: 50490

Middle Eastern (MID) AF: 0.583 AC: 3258 AN: 5586

European-Non Finnish (NFE) AF: 0.576 AC: 622766 AN: 1080644

Other (OTH) AF: 0.563 AC: 32882 AN: 58424

GnomAD4 genome AF: 0.595 AC: 90500 AN: 152050 Hom.: 27416 Cov.: 32 AF XY: 0.586 AC XY: 43563 AN XY: 74316

African (AFR) AF: 0.680 AC: 28197 AN: 41484

American (AMR) AF: 0.655 AC: 10011 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2017 AN: 3468

East Asian (EAS) AF: 0.486 AC: 2512 AN: 5172

South Asian (SAS) AF: 0.464 AC: 2236 AN: 4822

European-Finnish (FIN) AF: 0.455 AC: 4810 AN: 10566

Middle Eastern (MID) AF: 0.565 AC: 165 AN: 292

European-Non Finnish (NFE) AF: 0.570 AC: 38704 AN: 67950

Other (OTH) AF: 0.581 AC: 1224 AN: 2108

Alfa AF: 0.540 Hom.: 5117

Bravo AF: 0.618

Asia WGS AF: 0.491 AC: 1709 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 92% of patients studied by a panel of primary immunodeficiencies. Number of patients: 81. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.9
DANN	Benign	0.80
PhyloP100		-0.36
PromoterAI		-0.069	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: rs6694817; hg19: chr1-154401972; COSMIC: COSV59819073;