rs1063560

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002184.4(IL6ST):c.22C>G(p.Leu8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,586,984 control chromosomes in the GnomAD database, including 200 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 0.0081 ( 13 hom., cov: 32)

Exomes 𝑓: 0.012 ( 187 hom. )

Consequence

IL6ST
NM_002184.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.522

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=0.0030719936).

BP6

Variant 5-55976257-G-C is Benign according to our data. Variant chr5-55976257-G-C is described in ClinVar as [Benign]. Clinvar id is 1170704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00811 (1229/151460) while in subpopulation SAS AF= 0.033 (159/4820). AF 95% confidence interval is 0.0288. There are 13 homozygotes in gnomad4. There are 619 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6ST	NM_002184.4 link	c.22C>G	p.Leu8Val	missense_variant	Exon 3 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.22C>G	p.Leu8Val	missense_variant	Exon 3 of 17	1	NM_002184.4	ENSP00000370698.2		P40189-1

Frequencies

GnomAD3 genomes

AF:

0.00813

AC:

1230

AN:

151344

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00375

Gnomad ASJ

AF:

0.0231

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0330

Gnomad FIN

AF:

0.00278

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0116

Gnomad OTH

AF:

0.00869

GnomAD3 exomes

AF:

0.0117

AC:

2772

AN:

237792

Hom.:

AF XY:

0.0138

AC XY:

1782

AN XY:

129388

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00372

Gnomad ASJ exome

AF:

0.0253

Gnomad EAS exome

AF:

0.000177

Gnomad SAS exome

AF:

0.0343

Gnomad FIN exome

AF:

0.00223

Gnomad NFE exome

AF:

0.0117

Gnomad OTH exome

AF:

0.0138

GnomAD4 exome

AF:

0.0123

AC:

17650

AN:

1435524

Hom.:

187

Cov.:

AF XY:

0.0132

AC XY:

9441

AN XY:

714342

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.00390

Gnomad4 ASJ exome

AF:

0.0245

Gnomad4 EAS exome

AF:

0.000131

Gnomad4 SAS exome

AF:

0.0344

Gnomad4 FIN exome

AF:

0.00231

Gnomad4 NFE exome

AF:

0.0118

Gnomad4 OTH exome

AF:

0.0127

GnomAD4 genome

AF:

0.00811

AC:

1229

AN:

151460

Hom.:

Cov.:

AF XY:

0.00837

AC XY:

619

AN XY:

73936

show subpopulations

Gnomad4 AFR

AF:

0.00215

Gnomad4 AMR

AF:

0.00374

Gnomad4 ASJ

AF:

0.0231

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0330

Gnomad4 FIN

AF:

0.00278

Gnomad4 NFE

AF:

0.0116

Gnomad4 OTH

AF:

0.00860

Alfa

AF:

0.0121

Hom.:

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.0115

AC:

ExAC

AF:

0.0127

AC:

1548

Asia WGS

AF:

0.0230

AC:

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

IL6ST-related disorder

Benign:1

Nov 06, 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

0.066

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.29

DANN

Benign

0.13

DEOGEN2

Benign

0.12

T;T;.;T;.;T;T;.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.66

.;T;T;.;T;T;T;.;T

MetaRNN

Benign

0.0031

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L;L;L;L;.;.;L;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.26

N;N;N;.;N;N;N;N;.

REVEL

Benign

0.010

Sift

Benign

0.64

T;T;T;.;T;T;.;T;.

Sift4G

Benign

0.35

T;T;T;T;T;T;T;T;D

Polyphen

0.0

B;B;B;B;.;B;.;B;.

Vest4

0.027

MPC

0.12

ClinPred

0.0037

GERP RS

-1.1

Varity_R

0.024

gMVP

0.63

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