rs2228043

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002184.4(IL6ST):c.1189C>G(p.Leu397Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,611,530 control chromosomes in the GnomAD database, including 15,056 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.17 ( 3104 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11952 hom. )

Consequence

IL6ST
NM_002184.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0150

Variant links:

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]

IL6ST links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010964572).

BP6

Variant 5-55956103-G-C is Benign according to our data. Variant chr5-55956103-G-C is described in ClinVar as [Benign]. Clinvar id is 1168208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6ST	NM_002184.4 link	c.1189C>G	p.Leu397Val	missense_variant	Exon 10 of 17	ENST00000381298.7	NP_002175.2	P40189-1Q17RA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL6ST	ENST00000381298.7 link	c.1189C>G	p.Leu397Val	missense_variant	Exon 10 of 17	1	NM_002184.4	ENSP00000370698.2		P40189-1

Frequencies

GnomAD3 genomes

AF:

0.174

AC:

26455

AN:

152022

Hom.:

3085

Cov.:

show subpopulations

Gnomad AFR

AF:

0.324

Gnomad AMI

AF:

0.232

Gnomad AMR

AF:

0.123

Gnomad ASJ

AF:

0.131

Gnomad EAS

AF:

0.0329

Gnomad SAS

AF:

0.0706

Gnomad FIN

AF:

0.134

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.120

Gnomad OTH

AF:

0.166

GnomAD3 exomes

AF:

0.119

AC:

29908

AN:

251324

Hom.:

2327

AF XY:

0.115

AC XY:

15629

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.329

Gnomad AMR exome

AF:

0.0817

Gnomad ASJ exome

AF:

0.128

Gnomad EAS exome

AF:

0.0290

Gnomad SAS exome

AF:

0.0765

Gnomad FIN exome

AF:

0.126

Gnomad NFE exome

AF:

0.124

Gnomad OTH exome

AF:

0.126

GnomAD4 exome

AF:

0.120

AC:

175672

AN:

1459390

Hom.:

11952

Cov.:

AF XY:

0.119

AC XY:

86232

AN XY:

726234

show subpopulations

Gnomad4 AFR exome

AF:

0.332

Gnomad4 AMR exome

AF:

0.0857

Gnomad4 ASJ exome

AF:

0.129

Gnomad4 EAS exome

AF:

0.0356

Gnomad4 SAS exome

AF:

0.0745

Gnomad4 FIN exome

AF:

0.123

Gnomad4 NFE exome

AF:

0.121

Gnomad4 OTH exome

AF:

0.136

GnomAD4 genome

AF:

0.174

AC:

26517

AN:

152140

Hom.:

3104

Cov.:

AF XY:

0.170

AC XY:

12625

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.325

Gnomad4 AMR

AF:

0.123

Gnomad4 ASJ

AF:

0.131

Gnomad4 EAS

AF:

0.0331

Gnomad4 SAS

AF:

0.0700

Gnomad4 FIN

AF:

0.134

Gnomad4 NFE

AF:

0.120

Gnomad4 OTH

AF:

0.164

Alfa

AF:

0.128

Hom.:

1074

Bravo

AF:

0.183

TwinsUK

AF:

0.115

AC:

426

ALSPAC

AF:

0.121

AC:

466

ESP6500AA

AF:

0.316

AC:

1394

ESP6500EA

AF:

0.120

AC:

1035

ExAC

AF:

0.123

AC:

14885

Asia WGS

AF:

0.0920

AC:

321

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 24% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

IL6ST-related disorder

Benign:1

Nov 05, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.0

DANN

Benign

0.66

DEOGEN2

Benign

0.088

T;T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.040

.;T;.;T

MetaRNN

Benign

0.0011

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.5

N;N;N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

0.69

N;N;.;N

REVEL

Benign

0.015

Sift

Benign

0.33

T;T;.;T

Sift4G

Benign

0.45

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.014

MPC

0.12

ClinPred

0.00094

GERP RS

-0.89

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over