NM_000600.5:c.620G>C

Variant names:

• chr7-22731554-G-C
• NM_000600.5:c.620G>C

Variant summary

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

The NM_000600.5(IL6):​c.620G>C​(p.Arg207Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: IL6 NM_000600.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16

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, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6	NM_000600.5	c.620G>C	p.Arg207Thr	missense_variant	Exon 5 of 5	ENST00000258743.10	NP_000591.1
IL6	NM_001371096.1	c.551G>C	p.Arg184Thr	missense_variant	Exon 5 of 5		NP_001358025.1
IL6	NM_001318095.2	c.392G>C	p.Arg131Thr	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.620G>C	p.Arg207Thr	missense_variant	Exon 5 of 5	1	NM_000600.5	ENSP00000258743.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.620G>C (p.R207T) alteration is located in exon 5 (coding exon 5) of the IL6 gene. This alteration results from a G to C substitution at nucleotide position 620, causing the arginine (R) at amino acid position 207 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.39	T;T;.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	.;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.4	M;M;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-4.2	D;D;D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.89
MutPred		0.79		Loss of MoRF binding (P = 3e-04);Loss of MoRF binding (P = 3e-04);.;.;
MVP		0.91
MPC		0.86
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.95
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-22771173;