rs2069830

chr7-22727518-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000600.5(IL6):c.94C>T(p.Pro32Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00446 in 1,613,924 control chromosomes in the GnomAD database, including 266 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.023 (124 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (142 hom.)
• Consequence: IL6 NM_000600.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.265

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028251112).
• BP6: Variant 7-22727518-C-T is Benign according to our data. Variant chr7-22727518-C-T is described in ClinVar as [Benign]. Clinvar id is 768143.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.079 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL6	NM_000600.5	c.94C>T	p.Pro32Ser	missense_variant	2/5	ENST00000258743.10
IL6-AS1	NR_131935.1	n.53+50G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL6	ENST00000258743.10	c.94C>T	p.Pro32Ser	missense_variant	2/5	1	NM_000600.5	P1
IL6-AS1	ENST00000325042.2	n.53+50G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3556 AN: 152202 Hom.: 124 Cov.: 32

Gnomad AFR AF: 0.0815

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.00621 AC: 1554 AN: 250246 Hom.: 60 AF XY: 0.00459 AC XY: 621 AN XY: 135236

Gnomad AFR exome AF: 0.0828

Gnomad AMR exome AF: 0.00475

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00249 AC: 3642 AN: 1461604 Hom.: 142 Cov.: 32 AF XY: 0.00213 AC XY: 1548 AN XY: 727082

Gnomad4 AFR exome AF: 0.0852

Gnomad4 AMR exome AF: 0.00530

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000146

Gnomad4 OTH exome AF: 0.00585

GnomAD4 genome AF: 0.0233 AC: 3555 AN: 152320 Hom.: 124 Cov.: 32 AF XY: 0.0218 AC XY: 1620 AN XY: 74478

Gnomad4 AFR AF: 0.0812

Gnomad4 AMR AF: 0.00817

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00557 Hom.: 44

Bravo AF: 0.0277

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0751 AC: 331

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00750 AC: 911

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	7.2
Dann	Benign	0.47
DEOGEN2	Benign	0.065	T;T;T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
MetaRNN	Benign	0.0028	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.56	N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.27	T;T;T;T;T
Sift4G	Benign	0.60	T;T;T;T;T
Polyphen		0.0010	B;.;B;.;B
Vest4		0.016
MVP		0.54
MPC		0.17
ClinPred		0.0066	T
GERP RS		-0.35
Varity_R		0.036
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2069830; hg19: chr7-22767137;