rs2228043

Variant names:

• chr5-55956103-G-C
• rs2228043
• NM_002184.4:c.1189C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-55956103-G-C
• chr5-55956103-G-T

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.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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3104 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11952 hom.)
• Consequence: IL6ST NM_002184.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0150
• Publications: 43 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=0.0010964572).
• BP6: Variant 5-55956103-G-C is Benign according to our data. Variant chr5-55956103-G-C is described in ClinVar as Benign. ClinVar VariationId 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.

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.1189C>G	p.Leu397Val	missense	Exon 10 of 17	NP_002175.2
	IL6ST	NM_001364275.2		c.1189C>G	p.Leu397Val	missense	Exon 10 of 16	NP_001351204.1
	IL6ST	NM_001190981.2		c.1189C>G	p.Leu397Val	missense	Exon 10 of 16	NP_001177910.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6ST	ENST00000381298.7	TSL:1 MANE Select	c.1189C>G	p.Leu397Val	missense	Exon 10 of 17	ENSP00000370698.2
	IL6ST	ENST00000381294.8	TSL:1	c.1189C>G	p.Leu397Val	missense	Exon 10 of 16	ENSP00000370694.3
	IL6ST	ENST00000522633.2	TSL:1	c.*116C>G		3_prime_UTR	Exon 8 of 13	ENSP00000435399.1

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26455 AN: 152022 Hom.: 3085 Cov.: 32

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

GnomAD2 exomes AF: 0.119 AC: 29908 AN: 251324 AF XY: 0.115

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 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.: 30 AF XY: 0.119 AC XY: 86232 AN XY: 726234

African (AFR) AF: 0.332 AC: 11076 AN: 33378

American (AMR) AF: 0.0857 AC: 3834 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 3355 AN: 26106

East Asian (EAS) AF: 0.0356 AC: 1413 AN: 39678

South Asian (SAS) AF: 0.0745 AC: 6423 AN: 86208

European-Finnish (FIN) AF: 0.123 AC: 6578 AN: 53408

Middle Eastern (MID) AF: 0.151 AC: 872 AN: 5760

European-Non Finnish (NFE) AF: 0.121 AC: 133917 AN: 1109828

Other (OTH) AF: 0.136 AC: 8204 AN: 60304

GnomAD4 genome AF: 0.174 AC: 26517 AN: 152140 Hom.: 3104 Cov.: 32 AF XY: 0.170 AC XY: 12625 AN XY: 74396

African (AFR) AF: 0.325 AC: 13465 AN: 41478

American (AMR) AF: 0.123 AC: 1881 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 453 AN: 3470

East Asian (EAS) AF: 0.0331 AC: 172 AN: 5190

South Asian (SAS) AF: 0.0700 AC: 338 AN: 4826

European-Finnish (FIN) AF: 0.134 AC: 1414 AN: 10588

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8191 AN: 67990

Other (OTH) AF: 0.164 AC: 346 AN: 2106

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	IL6ST-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.0
DANN	Benign	0.66
DEOGEN2	Benign	0.088	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.040	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.5	N
PhyloP100		-0.015
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.69	N
REVEL	Benign	0.015
Sift	Benign	0.33	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.014
MPC		0.12
ClinPred		0.00094	T
GERP RS		-0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.28
Mutation Taster		=81/19	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: rs2228043; hg19: chr5-55251931; COSMIC: COSV61140369; COSMIC: COSV61140369;