rs2228043

Positions:

• chr5-55956103-G-C

Variant summary

Our verdict is Benign. Variant got -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. 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 same amino acid change has been previously reported as Likely benignin UniProt.

• 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:3
• Conservation: PhyloP100: -0.0150

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]

ACMG classification

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/exons	MANE	UniProt
IL6ST	NM_002184.4	c.1189C>G	p.Leu397Val	missense_variant	10/17	ENST00000381298.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL6ST	ENST00000381298.7	c.1189C>G	p.Leu397Val	missense_variant	10/17	1	NM_002184.4	P1

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

GnomAD3 exomes AF: 0.119 AC: 29908 AN: 251324 Hom.: 2327 AF XY: 0.115 AC XY: 15629 AN XY: 135834

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

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.: 32 AF XY: 0.170 AC XY: 12625 AN XY: 74396

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 05, 2019

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.024	N
MetaRNN	Benign	0.0011	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.5	N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.23	T
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	T
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

Other links and lift over

dbSNP: rs2228043; hg19: chr5-55251931; COSMIC: COSV61140369; COSMIC: COSV61140369;