chr7-22727515-C-T

Variant names:

• chr7-22727515-C-T
• rs142759801
• NM_000600.5:c.91C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000600.5(IL6):​c.91C>T​(p.Pro31Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. P31T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IL6 NM_000600.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0100
• Publications: 0 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-AS1 (HGNC:40301): (IL6 antisense RNA 1)

STEAP1B (HGNC:41907): (STEAP family member 1B) Predicted to be integral component of membrane. Predicted to be active in endosome and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11771241).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6	NM_000600.5	MANE Select	c.91C>T	p.Pro31Ser	missense	Exon 2 of 5	NP_000591.1	P05231
	IL6	NM_001371096.1		c.22C>T	p.Pro8Ser	missense splice_region	Exon 2 of 5	NP_001358025.1	B5MCZ3
	IL6	NM_001318095.2		c.-19+234C>T		intron	N/A	NP_001305024.1	B5MC21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6	ENST00000258743.10	TSL:1 MANE Select	c.91C>T	p.Pro31Ser	missense	Exon 2 of 5	ENSP00000258743.5	P05231
	IL6	ENST00000485300.1	TSL:1	c.253C>T	p.Pro85Ser	missense	Exon 1 of 4	ENSP00000512964.1	A0A8Q3SJL1
	IL6-AS1	ENST00000325042.2	TSL:1	n.53+53G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461654 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111910

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.2
DANN	Benign	0.90
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.010
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.087
Sift	Benign	0.59	T
Sift4G	Benign	0.60	T
Polyphen		0.38	B
Vest4		0.044
MVP		0.80
MPC		0.18
ClinPred		0.060	T
GERP RS		0.89
PromoterAI		-0.028	Neutral
Varity_R		0.031
gMVP		0.28
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs142759801; hg19: chr7-22767134;