rs281865192

chr12-88101183-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_025114.4(CEP290):c.2991+1655A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 151,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.00027 (0 hom., cov: 29)
• Consequence: CEP290 NM_025114.4 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24 O:2
• Conservation: PhyloP100: 0.0410

Genes affected

CEP290 (HGNC:29021): (centrosomal protein 290) This gene encodes a protein with 13 putative coiled-coil domains, a region with homology to SMC chromosome segregation ATPases, six KID motifs, three tropomyosin homology domains and an ATP/GTP binding site motif A. The protein is localized to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation. Mutations in this gene have been associated with Joubert syndrome and nephronophthisis and the presence of antibodies against this protein is associated with several forms of cancer. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-88101183-T-C is Pathogenic according to our data. Variant chr12-88101183-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88101183-T-C is described in Lovd as [Pathogenic]. Variant chr12-88101183-T-C is described in Lovd as [Pathogenic]. Variant chr12-88101183-T-C is described in Lovd as [Likely_pathogenic]. Variant chr12-88101183-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4	c.2991+1655A>G		intron_variant		ENST00000552810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6	c.2991+1655A>G		intron_variant		1	NM_025114.4	P4

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 151912 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000725

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: 0.000559

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.000270 AC: 41 AN: 151912 Hom.: 0 Cov.: 29 AF XY: 0.000148 AC XY: 11 AN XY: 74202

Gnomad4 AFR AF: 0.0000725

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: 0.000559

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000207 Hom.: 0

Bravo AF: 0.000295

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:24 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2023	Published functional studies demonstrate a damaging effect resulting in the insertion of an aberrant exon into approximately half of CEP290 transcripts and reduced CEP290 mRNA levels in comparison to wild type (Garanto et al., 2015; Gerard et al., 2012); This variant is associated with the following publications: (PMID: 22842229, 20683928, 20805370, 27106101, 31429209, 34196655, 23591405, 19823873, 24767827, 17564967, 17345604, 20130272, 23344081, 23343883, 18682808, 25761237, 20690115, 22355252, 28224992, 24223178, 29186038, 29178642, 30576320, 30193310, 31087526, 30559420, 31734136, 34327195, 32531858, 32865313, 29398085, 29518907, 33726816, 32037395, 31816670, 28619647, 28510626, 16909394) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Leber congenital amaurosis 10 Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2007	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Mar 29, 2012	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The CEP290 c.2991+1655A>G 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: PS4, PS3, PM2, PM3, PP1, PP5. Based on this evidence we have classified this variant as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -

CEP290-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 12, 2023	The CEP290 c.2991+1655A>G variant is predicted to interfere with splicing. This variant (also referred to as IVS26+1655A>G) has been reported to create a strong splice-donor site and insert a cryptic exon in the CEP290 messenger RNA (den Hollander et al. 2006. PubMed ID: 16909394). This variant has been reported, in the homozygous or compound heterozygous state along with a second CEP290 variant, in 16 of 76 unrelated patients with autosomal recessive Leber congenital amaurosis (den Hollander et al. 2006. PubMed ID: 16909394). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/1337/). Given the evidence, we interpret c.2991+1655A>G as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 16, 2021	Variant summary: CEP290 c.2991+1655A>G is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic intronic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and leads to insertion of a cryptic exon encoding a premature stop codon (den Hollander_2006). The variant allele was found at a frequency of 0.00013 in 31310 control chromosomes. c.2991+1655A>G has been reported in the literature in multiple individuals affected with CEP290-Related Disorders, namely Leber Congenital Amaurosis (example, den Hollander_2006). These data indicate that the variant is very likely to be associated with disease. Functional studies have reported ciliary and axonemal defects in patients with this variant (Gerard_2012). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Joubert syndrome 5 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PM3,PP3,PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Oct 16, 2023	- -

Leber congenital amaurosis Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 23, 2017

- -

Bardet-Biedl syndrome 14 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 28, 2023

- -

Joubert syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change falls in intron 26 of the CEP290 gene. It does not directly change the encoded amino acid sequence of the CEP290 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs281865192, gnomAD 0.02%). This variant has been observed in individual(s) with Leber congenital amaurosis (PMID: 16909394, 17345604, 17964524). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS26+1655A>G and p.Cys998X. ClinVar contains an entry for this variant (Variation ID: 1337). Studies have shown that this variant results in insertion of 128bp of intronic sequence between exons 26 and 27 and introduces a premature termination codon (PMID: 16909394, 23344081). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Aug 03, 2020

The variant c.2991+1655A>G, was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was not maternal.The variant likely explains the NDD in this individual. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 25, 2019

- -

Senior-Loken syndrome 6;C1857780:Joubert syndrome 5;C1857821:Leber congenital amaurosis 10;C1970161:Meckel syndrome, type 4;C2673874:Bardet-Biedl syndrome 14 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 13, 2022

- -

Retinitis pigmentosa Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Sep 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	10
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs281865192; hg19: chr12-88494960;