7-22729691-G-A

Variant names:

• chr7-22729691-G-A
• rs2069842
• NM_000600.5:c.471+31G>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.471+31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00424 in 1,614,056 control chromosomes in the GnomAD database, including 240 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 0.022 (124 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (116 hom.)
• Consequence: IL6 NM_000600.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• Publications: 24 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=0.0017405152).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0735 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6	NM_000600.5	MANE Select	c.471+31G>A		intron	N/A	NP_000591.1
	IL6	NM_001371096.1		c.402+31G>A		intron	N/A	NP_001358025.1
	IL6	NM_001318095.2		c.243+31G>A		intron	N/A	NP_001305024.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6	ENST00000258743.10	TSL:1 MANE Select	c.471+31G>A		intron	N/A	ENSP00000258743.5
	IL6	ENST00000485300.1	TSL:1	c.633+31G>A		intron	N/A	ENSP00000512964.1
	IL6	ENST00000406575.1	TSL:2	c.502G>A	p.Val168Met	missense	Exon 4 of 4	ENSP00000385227.1

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3336 AN: 152192 Hom.: 124 Cov.: 32

Gnomad AFR AF: 0.0760

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0162

GnomAD2 exomes AF: 0.00618 AC: 1552 AN: 251248 AF XY: 0.00434

Gnomad AFR exome AF: 0.0800

Gnomad AMR exome AF: 0.00477

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00240 AC: 3504 AN: 1461746 Hom.: 116 Cov.: 33 AF XY: 0.00208 AC XY: 1511 AN XY: 727172

African (AFR) AF: 0.0791 AC: 2646 AN: 33472

American (AMR) AF: 0.00492 AC: 220 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 61 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.000185 AC: 206 AN: 1111918

Other (OTH) AF: 0.00568 AC: 343 AN: 60388

GnomAD4 genome AF: 0.0219 AC: 3334 AN: 152310 Hom.: 124 Cov.: 32 AF XY: 0.0213 AC XY: 1583 AN XY: 74482

African (AFR) AF: 0.0757 AC: 3147 AN: 41550

American (AMR) AF: 0.00817 AC: 125 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68024

Other (OTH) AF: 0.0161 AC: 34 AN: 2116

Alfa AF: 0.0171 Hom.: 80

Bravo AF: 0.0251

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0713 AC: 314

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00737 AC: 895

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000475

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.52
DANN	Benign	0.54
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
PhyloP100		-1.3
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.027
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.020	D
Polyphen		0.0060	B
Vest4		0.13
MVP		0.36
ClinPred		0.0078	T
GERP RS		-5.3
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: rs2069842; hg19: chr7-22769310;