5-55966832-A-G

Variant names:

• chr5-55966832-A-G
• rs10940495
• NM_002184.4:c.491+1444T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002184.4(IL6ST):​c.491+1444T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 152,050 control chromosomes in the GnomAD database, including 4,142 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (4142 hom., cov: 31)
• Consequence: IL6ST NM_002184.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.542
• Publications: 26 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.276 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6ST	NM_002184.4	MANE Select	c.491+1444T>C		intron	N/A	NP_002175.2
	IL6ST	NM_001364275.2		c.491+1444T>C		intron	N/A	NP_001351204.1
	IL6ST	NM_001190981.2		c.491+1444T>C		intron	N/A	NP_001177910.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6ST	ENST00000381298.7	TSL:1 MANE Select	c.491+1444T>C		intron	N/A	ENSP00000370698.2
	IL6ST	ENST00000381294.8	TSL:1	c.491+1444T>C		intron	N/A	ENSP00000370694.3
	IL6ST	ENST00000522633.2	TSL:1	c.491+1444T>C		intron	N/A	ENSP00000435399.1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32962 AN: 151932 Hom.: 4144 Cov.: 31

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.0958

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.227

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.217 AC: 32972 AN: 152050 Hom.: 4142 Cov.: 31 AF XY: 0.215 AC XY: 15993 AN XY: 74334

African (AFR) AF: 0.106 AC: 4390 AN: 41490

American (AMR) AF: 0.187 AC: 2862 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1102 AN: 3468

East Asian (EAS) AF: 0.0955 AC: 495 AN: 5184

South Asian (SAS) AF: 0.274 AC: 1319 AN: 4818

European-Finnish (FIN) AF: 0.293 AC: 3080 AN: 10524

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.279 AC: 18970 AN: 67968

Other (OTH) AF: 0.228 AC: 482 AN: 2112

Alfa AF: 0.259 Hom.: 15557

Bravo AF: 0.203

Asia WGS AF: 0.191 AC: 666 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	10
DANN	Benign	0.68
PhyloP100		-0.54
Mutation Taster		=100/0	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: rs10940495; hg19: chr5-55262660; COSMIC: COSV61140483;