rs1063560

chr5-55976257-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0081 (13 hom., cov: 32)
  • Exomes 𝑓: 0.012 (187 hom.)
• Consequence: IL6ST NM_002184.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.522

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=0.0030719936).
• 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 GnomAd at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL6ST	NM_002184.4	c.22C>G	p.Leu8Val	missense_variant	3/17	ENST00000381298.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL6ST	ENST00000381298.7	c.22C>G	p.Leu8Val	missense_variant	3/17	1	NM_002184.4	P1

Frequencies

GnomAD3 genomes AF: 0.00813 AC: 1230 AN: 151344 Hom.: 13 Cov.: 32

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.: 45 AF XY: 0.0138 AC XY: 1782 AN XY: 129388

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.: 28 AF XY: 0.0132 AC XY: 9441 AN XY: 714342

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.: 13 Cov.: 32 AF XY: 0.00837 AC XY: 619 AN XY: 73936

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.: 10

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.0115 AC: 99

ExAC AF: 0.0127 AC: 1548

Asia WGS AF: 0.0230 AC: 78 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IL6ST-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 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	0.066
BayesDel_addAF	Benign	-0.62	T
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	N
MetaRNN	Benign	0.0031	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L;L;L;L;.;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
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	T
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

Other links and lift over

dbSNP: rs1063560; hg19: chr5-55272085;