Genetic Variant IL6:c.*462C>T (chr7-22732035-C-T) – 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.*462C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0574 in 145,996 control chromosomes in the GnomAD database, including 313 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 0.057 ( 311 hom., cov: 30)

Exomes 𝑓: 0.23 ( 2 hom. )

Consequence

IL6
NM_000600.5 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.271

Publications

52 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:

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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=-0.86).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0888 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000600.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IL6	NM_000600.5	MANE Select	c.*462C>T	downstream_gene	N/A	NP_000591.1	P05231
IL6	NM_001371096.1		c.*462C>T	downstream_gene	N/A	NP_001358025.1	B5MCZ3
IL6	NM_001318095.2		c.*462C>T	downstream_gene	N/A	NP_001305024.1	B5MC21

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IL6	ENST00000258743.10	TSL:1 MANE Select	c.*462C>T	downstream_gene	N/A	ENSP00000258743.5	P05231
IL6	ENST00000404625.5	TSL:5	c.*462C>T	downstream_gene	N/A	ENSP00000385675.1	P05231
IL6	ENST00000964192.1		c.*462C>T	downstream_gene	N/A	ENSP00000634251.1

Frequencies

GnomAD3 genomes

AF:

0.0574

AC:

8380

AN:

145938

Hom.:

312

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0176

Gnomad AMI

AF:

0.0593

Gnomad AMR

AF:

0.0382

Gnomad ASJ

AF:

0.0668

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.0218

Gnomad FIN

AF:

0.0665

Gnomad MID

AF:

0.0649

Gnomad NFE

AF:

0.0907

Gnomad OTH

AF:

0.0498

GnomAD4 exome

AF:

0.229

AC:

AN:

Hom.:

Cov.:

AF XY:

0.214

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.229

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0574

AC:

8374

AN:

145948

Hom.:

311

Cov.:

AF XY:

0.0541

AC XY:

3836

AN XY:

70860

show subpopulations

African (AFR)

AF:

0.0175

AC:

698

AN:

39832

American (AMR)

AF:

0.0380

AC:

547

AN:

14376

Ashkenazi Jewish (ASJ)

AF:

0.0668

AC:

230

AN:

3442

East Asian (EAS)

AF:

0.000197

AC:

AN:

5078

South Asian (SAS)

AF:

0.0215

AC:

101

AN:

4706

European-Finnish (FIN)

AF:

0.0665

AC:

563

AN:

8460

Middle Eastern (MID)

AF:

0.0599

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.0907

AC:

6066

AN:

66896

Other (OTH)

AF:

0.0495

AC:

AN:

1980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

387

773

1160

1546

1933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0609

Hom.:

101

Bravo

AF:

0.0537

Asia WGS

AF:

0.0170

AC:

AN:

3436

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.9

(source)

DANN

Benign

0.71

PhyloP100

-0.27

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over