rs750962965
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001023570.4(IQCB1):c.424_425del(p.Phe142ProfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.000185 in 1,608,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 0 hom. )
Consequence
IQCB1
NM_001023570.4 frameshift
NM_001023570.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.26
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
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 3-121808977-GAA-G is Pathogenic according to our data. Variant chr3-121808977-GAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 1831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-121808977-GAA-G is described in Lovd as [Likely_pathogenic]. Variant chr3-121808977-GAA-G is described in Lovd as [Likely_pathogenic]. Variant chr3-121808977-GAA-G is described in Lovd as [Pathogenic]. Variant chr3-121808977-GAA-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IQCB1 | NM_001023570.4 | c.424_425del | p.Phe142ProfsTer5 | frameshift_variant | 6/15 | ENST00000310864.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IQCB1 | ENST00000310864.11 | c.424_425del | p.Phe142ProfsTer5 | frameshift_variant | 6/15 | 1 | NM_001023570.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000126 AC: 19AN: 151250Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000997 AC: 25AN: 250638Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135534
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GnomAD4 exome AF: 0.000191 AC: 279AN: 1457492Hom.: 0 AF XY: 0.000194 AC XY: 141AN XY: 725218
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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:6
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The IQCB1 c.424_425delTT (p.Phe142ProfsTer5) variant is a frameshift variant that is predicted to result in premature termination of the protein. The p.Phe142ProfsTer5 variant has been reported in three studies in which it is found in a total of nine individuals with Senior Loken syndrome, including in seven patients in a homozygous state and in two patients in a compound heterozygous state who both carried a null variant on the second allele (Otto et al. 2005; Estrada-Cuzcano et al. 2011; Halbritter et al. 2013). The p.Phe142ProfsTer5 variant was absent from 347 control subjects but is reported at a frequency of 0.00023 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Phe142ProfsTer5 variant is classified as pathogenic for Senior Loken syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The IQCB1 c.424_425del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3. Based on this evidence we have classified this variant as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 11, 2011 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Sep 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 17, 2023 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 23, 2021 | Frameshift 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: 23446637, 21866095, 15723066, 28832562, 20881296, 29453417, 31980526, 32581362) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2021 | - - |
Leber congenital amaurosis Pathogenic:1
Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Nephronophthisis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | This sequence change creates a premature translational stop signal (p.Phe142Profs*5) 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). This variant is present in population databases (rs750962965, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis and Senior-L√∏ken syndrome (PMID: 15723066, 20881296, 21866095, 23188109, 24625443, 28041643, 28832562). This variant is also known as c.224_225delTT, p.F142fsX146. ClinVar contains an entry for this variant (Variation ID: 1831). For these reasons, this variant has been classified as Pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 06, 2017 | - - |
Computational scores
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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