Genetic Variant IL6R:c.1067-867A>G (chr1-154453621-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000565.4(IL6R):c.1067-867A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 152,106 control chromosomes in the GnomAD database, including 28,054 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 0.60 ( 28054 hom., cov: 33)

Consequence

IL6R
NM_000565.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.40

Publications

27 publications found

Variant links:

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

IL6R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6R	NM_000565.4 link	c.1067-867A>G		intron_variant	Intron 8 of 9	ENST00000368485.8	NP_000556.1	P08887-1A0N0L5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
IL6R	ENST00000368485.8 link	c.1067-867A>G	intron_variant	Intron 8 of 9	1	NM_000565.4	ENSP00000357470.3	P08887-1
IL6R	ENST00000344086.8 link	c.1066+3641A>G	intron_variant	Intron 8 of 8	1		ENSP00000340589.4	P08887-2
IL6R	ENST00000515190.1 link	c.473-867A>G	intron_variant	Intron 5 of 5	2		ENSP00000423036.1	H0Y949
IL6R	ENST00000507256.1 link	n.265-867A>G	intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.600

AC:

91207

AN:

151988

Hom.:

28010

Cov.:

show subpopulations

Gnomad AFR

AF:

0.705

Gnomad AMI

AF:

0.670

Gnomad AMR

AF:

0.654

Gnomad ASJ

AF:

0.604

Gnomad EAS

AF:

0.465

Gnomad SAS

AF:

0.471

Gnomad FIN

AF:

0.445

Gnomad MID

AF:

0.579

Gnomad NFE

AF:

0.568

Gnomad OTH

AF:

0.585

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.600

AC:

91309

AN:

152106

Hom.:

28054

Cov.:

AF XY:

0.591

AC XY:

43921

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.705

AC:

29267

AN:

41514

American (AMR)

AF:

0.654

AC:

9977

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.604

AC:

2096

AN:

3472

East Asian (EAS)

AF:

0.465

AC:

2405

AN:

5170

South Asian (SAS)

AF:

0.471

AC:

2274

AN:

4828

European-Finnish (FIN)

AF:

0.445

AC:

4705

AN:

10578

Middle Eastern (MID)

AF:

0.582

AC:

171

AN:

294

European-Non Finnish (NFE)

AF:

0.568

AC:

38577

AN:

67974

Other (OTH)

AF:

0.584

AC:

1229

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1863

3726

5590

7453

9316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

752

1504

2256

3008

3760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.590

Hom.:

5566

Bravo

AF:

0.624

Asia WGS

AF:

0.484

AC:

1687

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.056

(source)

DANN

Benign

0.24

PhyloP100

-2.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over