Genetic Variant IL6:c.471+494G>C (chr7-22730154-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_000600.5(IL6):c.471+494G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0337 in 985,330 control chromosomes in the GnomAD database, including 1,366 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 0.071 ( 791 hom., cov: 32)

Exomes 𝑓: 0.027 ( 575 hom. )

Consequence

IL6
NM_000600.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.124

Publications

20 publications found

Variant links:

Genes affected

IL6 (HGNC:6018): (interleukin 6) This gene encodes a cytokine that functions in inflammation and the maturation of B cells. In addition, the encoded protein has been shown to be an endogenous pyrogen capable of inducing fever in people with autoimmune diseases or infections. The protein is primarily produced at sites of acute and chronic inflammation, where it is secreted into the serum and induces a transcriptional inflammatory response through interleukin 6 receptor, alpha. The functioning of this gene is implicated in a wide variety of inflammation-associated disease states, including suspectibility to diabetes mellitus and systemic juvenile rheumatoid arthritis. Elevated levels of the encoded protein have been found in virus infections, including COVID-19 (disease caused by SARS-CoV-2). [provided by RefSeq, Aug 2020]

IL6 Gene-Disease associations (from GenCC):

Kaposi sarcoma, susceptibility to
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P

IL6 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=-0.83).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
IL6	NM_000600.5 link	c.471+494G>C	intron_variant	Intron 4 of 4	ENST00000258743.10	NP_000591.1
IL6	XM_005249745.6 link	c.*368G>C	3_prime_UTR_variant	Exon 3 of 3		XP_005249802.1
IL6	NM_001371096.1 link	c.402+494G>C	intron_variant	Intron 4 of 4		NP_001358025.1
IL6	NM_001318095.2 link	c.243+494G>C	intron_variant	Intron 3 of 3		NP_001305024.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL6	ENST00000258743.10 link	c.471+494G>C		intron_variant	Intron 4 of 4	1	NM_000600.5	ENSP00000258743.5

Frequencies

GnomAD3 genomes

AF:

0.0706

AC:

10739

AN:

152116

Hom.:

787

Cov.:

show subpopulations

Gnomad AFR

AF:

0.180

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0568

Gnomad ASJ

AF:

0.0701

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0571

Gnomad FIN

AF:

0.0218

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0222

Gnomad OTH

AF:

0.0587

GnomAD4 exome

AF:

0.0269

AC:

22404

AN:

833096

Hom.:

575

Cov.:

AF XY:

0.0264

AC XY:

10161

AN XY:

384702

show subpopulations

African (AFR)

AF:

0.200

AC:

3156

AN:

15784

American (AMR)

AF:

0.0630

AC:

AN:

984

Ashkenazi Jewish (ASJ)

AF:

0.0699

AC:

360

AN:

5152

East Asian (EAS)

AF:

0.000826

AC:

AN:

3630

South Asian (SAS)

AF:

0.0522

AC:

859

AN:

16458

European-Finnish (FIN)

AF:

0.0181

AC:

AN:

276

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

1620

European-Non Finnish (NFE)

AF:

0.0223

AC:

16976

AN:

761894

Other (OTH)

AF:

0.0340

AC:

928

AN:

27298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1085

2169

3254

4338

5423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1000

2000

3000

4000

5000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0707

AC:

10768

AN:

152234

Hom.:

791

Cov.:

AF XY:

0.0696

AC XY:

5182

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.180

AC:

7491

AN:

41510

American (AMR)

AF:

0.0572

AC:

875

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0701

AC:

243

AN:

3468

East Asian (EAS)

AF:

0.00135

AC:

AN:

5182

South Asian (SAS)

AF:

0.0570

AC:

275

AN:

4826

European-Finnish (FIN)

AF:

0.0218

AC:

231

AN:

10608

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0222

AC:

1511

AN:

68022

Other (OTH)

AF:

0.0577

AC:

122

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

445

891

1336

1782

2227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.0506

Hom.:

Bravo

AF:

0.0796

Asia WGS

AF:

0.0390

AC:

137

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

7.1

(source)

DANN

Benign

0.75

PhyloP100

-0.12

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over