rs121918244
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001023570.4(IQCB1):c.1381C>T(p.Arg461Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,613,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000044 ( 0 hom. )
Consequence
IQCB1
NM_001023570.4 stop_gained
NM_001023570.4 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 2.27
Genes affected
IQCB1 (HGNC:28949): (IQ motif containing B1) This gene encodes a nephrocystin protein that interacts with calmodulin and the retinitis pigmentosa GTPase regulator protein. The encoded protein has a central coiled-coil region and two calmodulin-binding IQ domains. It is localized to the primary cilia of renal epithelial cells and connecting cilia of photoreceptor cells. The protein is thought to play a role in ciliary function. Defects in this gene result in Senior-Loken syndrome type 5. Alternative splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 6. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-121781772-G-A is Pathogenic according to our data. Variant chr3-121781772-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-121781772-G-A is described in Lovd as [Pathogenic]. Variant chr3-121781772-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| IQCB1 | NM_001023570.4 | c.1381C>T | p.Arg461Ter | stop_gained | 13/15 | ENST00000310864.11 | NP_001018864.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| IQCB1 | ENST00000310864.11 | c.1381C>T | p.Arg461Ter | stop_gained | 13/15 | 1 | NM_001023570.4 | ENSP00000311505 | P1 | |
| IQCB1 | ENST00000349820.10 | c.982C>T | p.Arg328Ter | stop_gained | 10/12 | 1 | ENSP00000323756 | |||
| IQCB1 | ENST00000393650.7 | c.*359C>T | 3_prime_UTR_variant, NMD_transcript_variant | 12/14 | 5 | ENSP00000377261 |
Frequencies
GnomAD3 genomes 0.000118 AC: 18AN: 151978Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251372Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135854
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GnomAD4 exome AF: 0.0000445 AC: 65AN: 1461388Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26AN XY: 727012
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GnomAD4 genome 0.000118 AC: 18AN: 152094Hom.: 0 Cov.: 31 AF XY: 0.0000941 AC XY: 7AN XY: 74354
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Senior-Loken syndrome 5 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 07, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 11, 2011 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 15, 2022 | Published functional studies demonstrate the mutant protein is incompetent in binding to Cep290, mislocalized, and unable to rescue ciliogenesis (Barbelanne et al., 2013); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21866095, 25525159, 30586318, 23446637, 15723066, 21220633, 23847139, 31456290, 32581362, 33512896, 31589614, 36426739, 33535056, 28041643, 20881296, 28559085) - |
| Pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 21, 2013 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 25, 2023 | The c.1381C>T (p.R461*) alteration, located in exon 13 (coding exon 11) of the IQCB1 gene, consists of a C to T substitution at nucleotide position 1381. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 461. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.006% (18/282708) total alleles studied. The highest observed frequency was 0.154% (16/10370) of Ashkenazi Jewish alleles. This variant has been reported homozygous or compound heterozygous in multiple individuals with features consistent with IQCB1-related Senior-Loken syndrome (Otto, 2005; Otto, 2008; Chaki, 2011; Cideciyan, 2011; Estrada-Cuzcano, 2011; Stone, 2011; Halbritter, 2012; Coppieters, 2014; Wang, 2013; Rishi, 2021). One functional study has demonstrated that p.R461* disrupts protein-protein interactions with Cep290, causes mislocalization, and inhibits cilia formation in cells (Barbelanne, 2013). Based on the available evidence, this alteration is classified as pathogenic. - |
Nephronophthisis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 26, 2023 | This sequence change creates a premature translational stop signal (p.Arg461*) in the IQCB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IQCB1 are known to be pathogenic (PMID: 15723066, 21901789, 23559409, 28041643). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Leber congenital amaurosis and/or Senior-Loken syndrome (PMID: 15723066, 20881296, 21220633, 21245082, 21866095, 23188109, 23847139, 24625443). ClinVar contains an entry for this variant (Variation ID: 1830). For these reasons, this variant has been classified as Pathogenic. - |
IQCB1-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 15, 2023 | The IQCB1 c.1381C>T variant is predicted to result in premature protein termination (p.Arg461*). This variant has been reported in homozygous or compound heterozygous states in multiple individuals with Senior-Loken syndrome, Leber congenital amaurosis and/or other retinal diseases (Otto et al. 2005. PubMed ID: 15723066; Estrada-Cuzcano et al. 2011. PubMed ID: 20881296; Stone et al. 2017. PubMed ID: 28559085. Table S1). This variant is reported in 0.15% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-121500619-G-A). However, the frequency data for this variant is considered unreliable since metrics indicate poor data quality at this position in the gnomAD database. Nonsense variants in IQCB1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Renal dysplasia and retinal aplasia Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Retinal dystrophy Pathogenic:1
| Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at