rs2228044

Variant names:

• chr5-55968325-C-A
• rs2228044
• NM_002184.4:c.442G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-55968325-C-A
• chr5-55968325-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002184.4(IL6ST):​c.442G>T​(p.Gly148Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G148R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IL6ST NM_002184.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.73
• Publications: 50 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14086324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6ST	NM_002184.4	c.442G>T	p.Gly148Cys	missense_variant	Exon 5 of 17	ENST00000381298.7	NP_002175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL6ST	ENST00000381298.7	c.442G>T	p.Gly148Cys	missense_variant	Exon 5 of 17	1	NM_002184.4	ENSP00000370698.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449262 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 720884

African (AFR) AF: 0.00 AC: 0 AN: 32306

American (AMR) AF: 0.00 AC: 0 AN: 41314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25794

East Asian (EAS) AF: 0.00 AC: 0 AN: 39402

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107936

Other (OTH) AF: 0.00 AC: 0 AN: 60020

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 409

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T;T;.;T;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.11
LIST_S2	Benign	0.0	.;T;T;.;T;.
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.0	N;N;N;N;N;N
PhyloP100		4.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.90	N;N;N;.;N;N
Sift	Uncertain	0.0040	D;D;D;.;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D
Vest4		0.19
ClinPred		0.72	D
GERP RS		5.8
Varity_R		0.51
gMVP		0.67
Mutation Taster		=91/9	polymorphism

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: rs2228044; hg19: chr5-55264153;