5-55968325-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002184.4(IL6ST):c.442G>C(p.Gly148Arg) variant causes a missense change. The variant allele was found at a frequency of 0.13 in 1,599,816 control chromosomes in the GnomAD database, including 18,164 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 4933 hom., cov: 32)

Exomes 𝑓: 0.12 ( 13231 hom. )

Consequence

IL6ST
NM_002184.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.73

Publications

50 publications found

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 Gene-Disease associations (from GenCC):

hyper-IgE recurrent infection syndrome 4A, autosomal dominant
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hyper-IgE recurrent infection syndrome 4, autosomal recessive
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

IL6ST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019920468).

BP6

Variant 5-55968325-C-G is Benign according to our data. Variant chr5-55968325-C-G is described in ClinVar as Benign. ClinVar VariationId is 1098855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6ST	NM_002184.4 link	c.442G>C	p.Gly148Arg	missense_variant	Exon 5 of 17	ENST00000381298.7	NP_002175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL6ST	ENST00000381298.7 link	c.442G>C	p.Gly148Arg	missense_variant	Exon 5 of 17	1	NM_002184.4	ENSP00000370698.2

Frequencies

GnomAD3 genomes

AF:

0.206

AC:

31334

AN:

151818

Hom.:

4911

Cov.:

show subpopulations

Gnomad AFR

AF:

0.439

Gnomad AMI

AF:

0.232

Gnomad AMR

AF:

0.134

Gnomad ASJ

AF:

0.131

Gnomad EAS

AF:

0.0330

Gnomad SAS

AF:

0.0710

Gnomad FIN

AF:

0.133

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.120

Gnomad OTH

AF:

0.190

GnomAD2 exomes

AF:

0.127

AC:

30253

AN:

239150

AF XY:

0.120

show subpopulations

Gnomad AFR exome

AF:

0.441

Gnomad AMR exome

AF:

0.0842

Gnomad ASJ exome

AF:

0.126

Gnomad EAS exome

AF:

0.0280

Gnomad FIN exome

AF:

0.125

Gnomad NFE exome

AF:

0.122

Gnomad OTH exome

AF:

0.128

GnomAD4 exome

AF:

0.122

AC:

177277

AN:

1447880

Hom.:

13231

Cov.:

AF XY:

0.120

AC XY:

86735

AN XY:

720284

show subpopulations

African (AFR)

AF:

0.446

AC:

14343

AN:

32138

American (AMR)

AF:

0.0890

AC:

3675

AN:

41300

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

3293

AN:

25776

East Asian (EAS)

AF:

0.0354

AC:

1395

AN:

39400

South Asian (SAS)

AF:

0.0741

AC:

6182

AN:

83412

European-Finnish (FIN)

AF:

0.123

AC:

6543

AN:

53308

Middle Eastern (MID)

AF:

0.158

AC:

903

AN:

5732

European-Non Finnish (NFE)

AF:

0.120

AC:

132426

AN:

1106860

Other (OTH)

AF:

0.142

AC:

8517

AN:

59954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

6652

13303

19955

26606

33258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4900

9800

14700

19600

24500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.207

AC:

31407

AN:

151936

Hom.:

4933

Cov.:

AF XY:

0.201

AC XY:

14944

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.439

AC:

18180

AN:

41368

American (AMR)

AF:

0.134

AC:

2051

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

454

AN:

3470

East Asian (EAS)

AF:

0.0332

AC:

172

AN:

5174

South Asian (SAS)

AF:

0.0702

AC:

338

AN:

4812

European-Finnish (FIN)

AF:

0.133

AC:

1405

AN:

10540

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.120

AC:

8154

AN:

67980

Other (OTH)

AF:

0.188

AC:

397

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1097

2194

3290

4387

5484

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

286

572

858

1144

1430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.113

Hom.:

409

Bravo

AF:

0.219

TwinsUK

AF:

0.112

AC:

415

ALSPAC

AF:

0.119

AC:

460

ESP6500AA

AF:

0.422

AC:

1860

ESP6500EA

AF:

0.120

AC:

1028

ExAC

AF:

0.132

AC:

16050

Asia WGS

AF:

0.0980

AC:

344

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

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).

Hyper-IgE recurrent infection syndrome 4, autosomal recessive

Benign:1

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T;.;T;.;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.0

.;T;T;.;T;.

MetaRNN

Benign

0.0020

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.55

N;N;N;N;N;N

PhyloP100

4.7

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.010

N;N;N;.;N;N

REVEL

Benign

0.11

Sift

Benign

0.10

T;T;T;.;T;T

Sift4G

Uncertain

0.038

D;D;T;D;D;T

Vest4

0.054

ClinPred

0.027

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.66

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over