rs1063560

Variant names:

• chr5-55976257-G-C
• rs1063560
• NM_002184.4:c.22C>G

Variant summary

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

• 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:3
• Conservation: PhyloP100: -0.522
• Publications: 8 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=0.0030719936).
• BP6: Variant 5-55976257-G-C is Benign according to our data. Variant chr5-55976257-G-C is described in ClinVar as Benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6ST	NM_002184.4	MANE Select	c.22C>G	p.Leu8Val	missense	Exon 3 of 17	NP_002175.2
	IL6ST	NM_001364275.2		c.22C>G	p.Leu8Val	missense	Exon 3 of 16	NP_001351204.1
	IL6ST	NM_001190981.2		c.22C>G	p.Leu8Val	missense	Exon 3 of 16	NP_001177910.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6ST	ENST00000381298.7	TSL:1 MANE Select	c.22C>G	p.Leu8Val	missense	Exon 3 of 17	ENSP00000370698.2
	IL6ST	ENST00000381294.8	TSL:1	c.22C>G	p.Leu8Val	missense	Exon 3 of 16	ENSP00000370694.3
	IL6ST	ENST00000522633.2	TSL:1	c.22C>G	p.Leu8Val	missense	Exon 2 of 13	ENSP00000435399.1

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

GnomAD2 exomes AF: 0.0117 AC: 2772 AN: 237792 AF XY: 0.0138

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 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

African (AFR) AF: 0.00203 AC: 66 AN: 32436

American (AMR) AF: 0.00390 AC: 163 AN: 41838

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 627 AN: 25604

East Asian (EAS) AF: 0.000131 AC: 5 AN: 38146

South Asian (SAS) AF: 0.0344 AC: 2817 AN: 81898

European-Finnish (FIN) AF: 0.00231 AC: 122 AN: 52732

Middle Eastern (MID) AF: 0.0340 AC: 183 AN: 5378

European-Non Finnish (NFE) AF: 0.0118 AC: 12916 AN: 1098498

Other (OTH) AF: 0.0127 AC: 751 AN: 58994

GnomAD4 genome AF: 0.00811 AC: 1229 AN: 151460 Hom.: 13 Cov.: 32 AF XY: 0.00837 AC XY: 619 AN XY: 73936

African (AFR) AF: 0.00215 AC: 89 AN: 41464

American (AMR) AF: 0.00374 AC: 57 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0330 AC: 159 AN: 4820

European-Finnish (FIN) AF: 0.00278 AC: 29 AN: 10450

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0116 AC: 785 AN: 67532

Other (OTH) AF: 0.00860 AC: 18 AN: 2094

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

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)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.52
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.010
Sift	Benign	0.64	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.027
MPC		0.12
ClinPred		0.0037	T
GERP RS		-1.1
PromoterAI		-0.033	Neutral
Varity_R		0.024
gMVP		0.63
Mutation Taster		=99/1	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: rs1063560; hg19: chr5-55272085;