rs2069849

Positions:

• chr7-22731537-C-G
• chr7-22731537-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000600.5(IL6):​c.603C>G​(p.Phe201Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: IL6 NM_000600.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.748

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL6	NM_000600.5	c.603C>G	p.Phe201Leu	missense_variant	5/5	ENST00000258743.10	NP_000591.1
IL6	NM_001371096.1	c.534C>G	p.Phe178Leu	missense_variant	5/5		NP_001358025.1
IL6	NM_001318095.2	c.375C>G	p.Phe125Leu	missense_variant	4/4		NP_001305024.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL6	ENST00000258743.10	c.603C>G	p.Phe201Leu	missense_variant	5/5	1	NM_000600.5	ENSP00000258743	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;.;T
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.78	.;T;T;T
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.013	D
MutationAssessor	Benign	2.0	M;M;.;.
MutationTaster	Benign	0.014	P;P;P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.1	D;D;D;D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.088	T;T;T;T
Polyphen		1.0	D;D;.;.
Vest4		0.79
MutPred		0.89		Gain of disorder (P = 0.0637);Gain of disorder (P = 0.0637);.;.;
MVP		0.87
MPC		0.75
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.87
gMVP		0.74

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

LitVar

Other links and lift over

dbSNP: rs2069849; hg19: chr7-22771156;