rs398123538

chr3-121772604-CTG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001023570.4(IQCB1):c.1518_1519del(p.His506GlnfsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000973 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. H506H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: IQCB1 NM_001023570.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.09

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-121772604-CTG-C is Pathogenic according to our data. Variant chr3-121772604-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 93469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-121772604-CTG-C is described in Lovd as [Likely_pathogenic]. Variant chr3-121772604-CTG-C is described in Lovd as [Likely_pathogenic]. Variant chr3-121772604-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQCB1	NM_001023570.4	c.1518_1519del	p.His506GlnfsTer13	frameshift_variant	14/15	ENST00000310864.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQCB1	ENST00000310864.11	c.1518_1519del	p.His506GlnfsTer13	frameshift_variant	14/15	1	NM_001023570.4	P1
IQCB1	ENST00000349820.10	c.1119_1120del	p.His373GlnfsTer13	frameshift_variant	11/12	1
IQCB1	ENST00000393650.7	c.*496_*497del		3_prime_UTR_variant, NMD_transcript_variant	13/14	5

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000795 AC: 20 AN: 251420 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135884

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000101 AC: 147 AN: 1461894 Hom.: 0 AF XY: 0.000107 AC XY: 78 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74378

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000831

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Senior-Loken syndrome 5 Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2011	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The IQCB1 c.1518_1519del 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, PM3, PP1. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	May 23, 2017	The paternally-inherited c.1518_1519delCA is a frameshift variant, which is predicted to result in loss of function in the IQCB1 gene where loss of function is a known mechanism of Senior-Loken syndrome 5, OMIM 609254. The c.1518_1519delCA variant was observed to be in trans with a c.1465C>T pathogenic variant based on segregation analysis in the family. Both varaints are also present in the patient's similarly affected sister. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS) The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000093469, PMID:15723066). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000085, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 08, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2013	- -

Nephronophthisis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

This sequence change creates a premature translational stop signal (p.His506Glnfs*13) in the IQCB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 93 amino acid(s) of the IQCB1 protein. This variant is present in population databases (rs398123538, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Senior-Loken syndrome or Leber congenital amaurosis (PMID: 15723066, 20881296). ClinVar contains an entry for this variant (Variation ID: 93469). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs398123538; hg19: chr3-121491451;