rs2125112257

Variant names:

• chr3-9917359-G-A
• rs2125112257
• NM_153460.4:c.44G>A

Variant summary

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

The NM_153460.4(IL17RC):​c.44G>A​(p.Ser15Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S15S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IL17RC NM_153460.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03
• Publications: 0 publications found

Genes affected

IL17RC (HGNC:18358): (interleukin 17 receptor C) This gene encodes a single-pass type I membrane protein that shares similarity with the interleukin-17 receptor (IL-17RA). Unlike IL-17RA, which is predominantly expressed in hemopoietic cells, and binds with high affinity to only IL-17A, this protein is expressed in nonhemopoietic tissues, and binds both IL-17A and IL-17F with similar affinities. The proinflammatory cytokines, IL-17A and IL-17F, have been implicated in the progression of inflammatory and autoimmune diseases. Multiple alternatively spliced transcript variants encoding different isoforms have been detected for this gene, and it has been proposed that soluble, secreted proteins lacking transmembrane and intracellular domains may function as extracellular antagonists to cytokine signaling. [provided by RefSeq, Feb 2011]

IL17RC Gene-Disease associations (from GenCC):

• chronic mucocutaneous candidiasis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• candidiasis, familial, 9

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000288550 (HGNC:):

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=0.076713055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL17RC	NM_153460.4	c.44G>A	p.Ser15Asn	missense_variant	Exon 1 of 19	ENST00000403601.8	NP_703190.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL17RC	ENST00000403601.8	c.44G>A	p.Ser15Asn	missense_variant	Exon 1 of 19	1	NM_153460.4	ENSP00000384969.3
ENSG00000288550	ENST00000683484.1	n.44G>A		non_coding_transcript_exon_variant	Exon 1 of 24			ENSP00000507040.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Candidiasis, familial, 9 Uncertain:1

Jul 06, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with IL17RC-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 15 of the IL17RC protein (p.Ser15Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.027	.;.;.;T;.;.;.;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.74	T;.;T;T;T;T;T;T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.077	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.77	N;N;.;N;N;.;N;N;N
PhyloP100		1.0
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.46	.;N;N;N;.;N;N;N;N
REVEL	Benign	0.025
Sift	Benign	0.32	.;T;T;T;.;T;T;T;T
Sift4G	Benign	0.46	T;T;T;T;.;T;T;T;T
Polyphen		0.0020	.;B;.;B;B;.;B;.;.
Vest4		0.11
MutPred		0.36		Gain of glycosylation at S20 (P = 0.0545);Gain of glycosylation at S20 (P = 0.0545);Gain of glycosylation at S20 (P = 0.0545);Gain of glycosylation at S20 (P = 0.0545);Gain of glycosylation at S20 (P = 0.0545);Gain of glycosylation at S20 (P = 0.0545);Gain of glycosylation at S20 (P = 0.0545);Gain of glycosylation at S20 (P = 0.0545);Gain of glycosylation at S20 (P = 0.0545);
MVP		0.16
MPC		0.32
ClinPred		0.066	T
GERP RS		1.4
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.031
gMVP		0.099
Mutation Taster		=94/6	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: rs2125112257; hg19: chr3-9959043;