rs2228046

Positions:

• chr5-55954899-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002184.4(IL6ST):​c.1361T>C​(p.Ile454Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0158 in 1,612,922 control chromosomes in the GnomAD database, including 3,480 homozygotes. In-silico tool predicts 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 0.085 (1852 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (1628 hom.)
• Consequence: IL6ST NM_002184.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.33

Genes affected

IL6ST (HGNC:6021): (interleukin 6 cytokine family signal transducer) The protein encoded by this gene is a signal transducer shared by many cytokines, including interleukin 6 (IL6), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and oncostatin M (OSM). This protein functions as a part of the cytokine receptor complex. The activation of this protein is dependent upon the binding of cytokines to their receptors. vIL6, a protein related to IL6 and encoded by the Kaposi sarcoma-associated herpesvirus, can bypass the interleukin 6 receptor (IL6R) and directly activate this protein. Knockout studies in mice suggest that this gene plays a critical role in regulating myocyte apoptosis. Alternatively spliced transcript variants have been described. A related pseudogene has been identified on chromosome 17. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004338354).
• BP6: Variant 5-55954899-A-G is Benign according to our data. Variant chr5-55954899-A-G is described in ClinVar as [Benign]. Clinvar id is 1170115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL6ST	NM_002184.4	c.1361T>C	p.Ile454Thr	missense_variant	11/17	ENST00000381298.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL6ST	ENST00000381298.7	c.1361T>C	p.Ile454Thr	missense_variant	11/17	1	NM_002184.4	P1

Frequencies

GnomAD3 genomes AF: 0.0846 AC: 12874 AN: 152142 Hom.: 1846 Cov.: 32

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0342

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0645

GnomAD3 exomes AF: 0.0214 AC: 5373 AN: 251074 Hom.: 706 AF XY: 0.0153 AC XY: 2081 AN XY: 135690

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000590

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.00860 AC: 12560 AN: 1460662 Hom.: 1628 Cov.: 29 AF XY: 0.00735 AC XY: 5342 AN XY: 726722

Gnomad4 AFR exome AF: 0.300

Gnomad4 AMR exome AF: 0.0151

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000766

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000445

Gnomad4 OTH exome AF: 0.0205

GnomAD4 genome AF: 0.0848 AC: 12919 AN: 152260 Hom.: 1852 Cov.: 32 AF XY: 0.0821 AC XY: 6115 AN XY: 74456

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.0341

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.0639

Alfa AF: 0.0160 Hom.: 479

Bravo AF: 0.0964

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.282 AC: 1244

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0265 AC: 3215

Asia WGS AF: 0.0160 AC: 57 AN: 3476

EpiCase AF: 0.00120

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IL6ST-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;D;D
Eigen	Benign	-0.020
Eigen_PC	Benign	0.018
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.89	.;D;.
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.9	D;D;.
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D;D;.
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.31	B;B;B
Vest4		0.53
MPC		0.40
ClinPred		0.046	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.42
gMVP		0.81

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: rs2228046; hg19: chr5-55250727; COSMIC: COSV61140364; COSMIC: COSV61140364;