NM_000600.5:c.486T>A

Variant names:

• chr7-22731420-T-A
• rs13306435
• NM_000600.5:c.486T>A

Variant summary

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

The NM_000600.5(IL6):​c.486T>A​(p.Asp162Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,574,046 control chromosomes in the GnomAD database, including 660 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D162V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.019 (100 hom., cov: 31)
  • Exomes 𝑓: 0.015 (560 hom.)
• Consequence: IL6 NM_000600.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.208
• Publications: 46 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018788576).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6	NM_000600.5	c.486T>A	p.Asp162Glu	missense_variant	Exon 5 of 5	ENST00000258743.10	NP_000591.1
IL6	NM_001371096.1	c.417T>A	p.Asp139Glu	missense_variant	Exon 5 of 5		NP_001358025.1
IL6	NM_001318095.2	c.258T>A	p.Asp86Glu	missense_variant	Exon 4 of 4		NP_001305024.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL6	ENST00000258743.10	c.486T>A	p.Asp162Glu	missense_variant	Exon 5 of 5	1	NM_000600.5	ENSP00000258743.5

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2955 AN: 152162 Hom.: 99 Cov.: 31

Gnomad AFR AF: 0.00490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0977

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0285

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.0349

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00986

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0287 AC: 6745 AN: 235396 AF XY: 0.0246

Gnomad AFR exome AF: 0.00403

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.00111

Gnomad EAS exome AF: 0.0255

Gnomad FIN exome AF: 0.0362

Gnomad NFE exome AF: 0.00910

Gnomad OTH exome AF: 0.0266

GnomAD4 exome AF: 0.0150 AC: 21281 AN: 1421766 Hom.: 560 Cov.: 30 AF XY: 0.0144 AC XY: 10146 AN XY: 704528

African (AFR) AF: 0.00360 AC: 116 AN: 32226

American (AMR) AF: 0.132 AC: 5195 AN: 39250

Ashkenazi Jewish (ASJ) AF: 0.00100 AC: 25 AN: 24926

East Asian (EAS) AF: 0.0308 AC: 1198 AN: 38936

South Asian (SAS) AF: 0.00861 AC: 710 AN: 82456

European-Finnish (FIN) AF: 0.0377 AC: 1986 AN: 52728

Middle Eastern (MID) AF: 0.00395 AC: 22 AN: 5572

European-Non Finnish (NFE) AF: 0.0103 AC: 11225 AN: 1087354

Other (OTH) AF: 0.0138 AC: 804 AN: 58318

GnomAD4 genome AF: 0.0195 AC: 2965 AN: 152280 Hom.: 100 Cov.: 31 AF XY: 0.0226 AC XY: 1680 AN XY: 74476

African (AFR) AF: 0.00491 AC: 204 AN: 41550

American (AMR) AF: 0.0979 AC: 1497 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.0285 AC: 148 AN: 5186

South Asian (SAS) AF: 0.00726 AC: 35 AN: 4824

European-Finnish (FIN) AF: 0.0349 AC: 371 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00988 AC: 672 AN: 68022

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.00956 Hom.: 10

Bravo AF: 0.0232

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.00884 AC: 76

ExAC AF: 0.0251 AC: 3051

Asia WGS AF: 0.0250 AC: 85 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.1
DANN	Benign	0.48
DEOGEN2	Benign	0.13	T;T;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.50	.;T;T;T
MetaRNN	Benign	0.0019	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;N;.;.
PhyloP100		-0.21
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.97	N;N;N;N
REVEL	Benign	0.025
Sift	Benign	0.40	T;T;T;T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.0010	B;B;.;.
Vest4		0.0070
MutPred		0.10		Gain of MoRF binding (P = 0.1384);Gain of MoRF binding (P = 0.1384);.;.;
MPC		0.16
ClinPred		0.0034	T
GERP RS		-5.8
Varity_R		0.31
gMVP		0.064
Mutation Taster		=98/2	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: rs13306435; hg19: chr7-22771039; COSMIC: COSV51734003; COSMIC: COSV51734003;