Genetic Variant IL17RC:p.Ala324Ser (chr3-9928397-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_153460.4(IL17RC):c.970G>T(p.Ala324Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. A324T) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IL17RC
NM_153460.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.71

Publications

0 publications found

Variant links:

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)

IL17RC links:

ENSG00000288550 (HGNC:):

ENSG00000288550 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2726833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL17RC	NM_153460.4 link	c.970G>T	p.Ala324Ser	missense_variant	Exon 11 of 19	ENST00000403601.8	NP_703190.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL17RC	ENST00000403601.8 link	c.970G>T	p.Ala324Ser	missense_variant	Exon 11 of 19	1	NM_153460.4	ENSP00000384969.3
ENSG00000288550	ENST00000683484.1 link	n.886G>T		non_coding_transcript_exon_variant	Exon 10 of 24			ENSP00000507040.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451902

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721836

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33182

American (AMR)

AF:

0.00

AC:

AN:

43526

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25876

East Asian (EAS)

AF:

0.00

AC:

AN:

39556

South Asian (SAS)

AF:

0.00

AC:

AN:

85822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49858

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108338

Other (OTH)

AF:

0.00

AC:

AN:

60022

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

.;.;.;T;.;.;.;.;.

Eigen

Benign

-0.043

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.87

D;.;D;D;D;D;D;D;D

M_CAP

Benign

0.0087

MetaRNN

Benign

0.27

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

.;.;.;M;.;.;.;.;.

PhyloP100

3.7

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.5

.;N;N;N;.;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.21

.;T;D;T;.;D;T;T;T

Sift4G

Uncertain

0.032

D;D;D;D;.;D;D;D;D

Polyphen

0.94, 0.99, 0.88

.;P;.;D;P;.;P;.;.

Vest4

0.51

MutPred

0.28

.;.;.;Gain of disorder (P = 0.0777);.;.;.;.;.;

MVP

0.17

MPC

0.69

ClinPred

0.76

GERP RS

4.1

Varity_R

0.20

gMVP

0.57

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over