rs2228044

Variant names:

• chr5-55968325-C-G
• rs2228044
• NM_002184.4:c.442G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-55968325-C-G
• chr5-55968325-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.73
• Publications: 50 publications found

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)

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002184.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6ST	NM_002184.4	MANE Select	c.442G>C	p.Gly148Arg	missense	Exon 5 of 17	NP_002175.2
	IL6ST	NM_001364275.2		c.442G>C	p.Gly148Arg	missense	Exon 5 of 16	NP_001351204.1	A0A0A0N0L5
	IL6ST	NM_001190981.2		c.442G>C	p.Gly148Arg	missense	Exon 5 of 16	NP_001177910.1	P40189-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6ST	ENST00000381298.7	TSL:1 MANE Select	c.442G>C	p.Gly148Arg	missense	Exon 5 of 17	ENSP00000370698.2	P40189-1
	IL6ST	ENST00000381294.8	TSL:1	c.442G>C	p.Gly148Arg	missense	Exon 5 of 16	ENSP00000370694.3	P40189-3
	IL6ST	ENST00000522633.2	TSL:1	c.442G>C	p.Gly148Arg	missense	Exon 4 of 13	ENSP00000435399.1	P40189-2

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31334 AN: 151818 Hom.: 4911 Cov.: 32

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

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.: 29 AF XY: 0.120 AC XY: 86735 AN XY: 720284

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

GnomAD4 genome AF: 0.207 AC: 31407 AN: 151936 Hom.: 4933 Cov.: 32 AF XY: 0.201 AC XY: 14944 AN XY: 74270

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: 45 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8154 AN: 67980

Other (OTH) AF: 0.188 AC: 397 AN: 2110

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hyper-IgE recurrent infection syndrome 4, autosomal recessive (1)
-	-	1	IL6ST-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.042	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.55	N
PhyloP100		4.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.11
Sift	Benign	0.10	T
Sift4G	Uncertain	0.038	D
Polyphen		0.0	B
Vest4		0.054
MPC		0.15
ClinPred		0.027	T
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)

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

Other links and lift over

dbSNP: rs2228044; hg19: chr5-55264153; COSMIC: COSV61140381;