rs866982675

Positions:

• chr3-121781790-G-A
• chr3-121781790-G-C
• chr3-121781790-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001023570.4(IQCB1):​c.1363C>T​(p.Arg455*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,534 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: IQCB1 NM_001023570.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.50

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]

IQCB1 (HGNC:):

ACMG classification

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 3-121781790-G-A is Pathogenic according to our data. Variant chr3-121781790-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 504877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-121781790-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-121781790-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IQCB1	NM_001023570.4	c.1363C>T	p.Arg455*	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.1363C>T	p.Arg455*	stop_gained	13/15	1	NM_001023570.4	ENSP00000311505.6
IQCB1	ENST00000349820.10	c.964C>T	p.Arg322*	stop_gained	10/12	1		ENSP00000323756.7
IQCB1	ENST00000393650.7	n.*341C>T		non_coding_transcript_exon_variant	12/14	5		ENSP00000377261.3
IQCB1	ENST00000393650.7	n.*341C>T		3_prime_UTR_variant	12/14	5		ENSP00000377261.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461534 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727068

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Senior-Loken syndrome 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 19, 2024

- -

Nephronophthisis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 13, 2022

ClinVar contains an entry for this variant (Variation ID: 504877). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis and Senior-L√∏ken syndrome (PMID: 21220633, 21866095). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg455*) 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). For these reasons, this variant has been classified as Pathogenic. -

Renal dysplasia and retinal aplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 01, 2017

The p.Arg455X variant in IQCB1 (previously named NPHP5) has been reported in 1 h omozygous individual with Senior-L?ken syndrome (Chaki 2011), and in 1 child wit h Leber congenital amaurosis (LCA), in trans with another pathogenic IQCB1 varia nt (Stone 2011). This variant was absent from large population studies. This non sense variant leads to a premature termination codon at position 455 which is pr edicted to lead to a truncated or absent protein. Nonsense and other variants le ading to loss of function of the IQCB1 protein are an established cause of Senio r-L?ken syndrome. In summary, this variant meets our criteria to be classified a s pathogenic for Seni?r-Loken syndrome in an autosomal recessive manner based up on its presence in affected individuals, absence from controls, and predicted im pact on the protein. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.68	D
Vest4		0.18
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs866982675; hg19: chr3-121500637; COSMIC: COSV60437680;