rs281865192

Variant names:

• chr12-88101183-T-C
• rs281865192
• NM_025114.4:c.2991+1655A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. 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:26 O:2
• Conservation: PhyloP100: 0.0410
• Publications: 194 publications found

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]

CEP290 Gene-Disease associations (from GenCC):

• CEP290-related ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Bardet-Biedl syndrome 14

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis 10

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PP5: Variant 12-88101183-T-C is Pathogenic according to our data. Variant chr12-88101183-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.2991+1655A>G		intron_variant	Intron 26 of 53	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.2991+1655A>G		intron_variant	Intron 26 of 53	1	NM_025114.4	ENSP00000448012.1

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

African (AFR) AF: 0.0000725 AC: 3 AN: 41356

American (AMR) AF: 0.00 AC: 0 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000563 Hom.: 0

Bravo AF: 0.000295

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8 Other:1

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 11, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 02, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as the most common pathogenic variant among individuals of North American and North Western European background (PMID: 16909394, 34196655); 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 (PMID: 25761237, 23344081); This variant is associated with the following publications: (PMID: 22842229, 20683928, 20805370, 27106101, 31429209, 23591405, 19823873, 24767827, 17564967, 17345604, 20130272, 23344081, 23343883, 18682808, 20690115, 22355252, 28224992, 24223178, 29186038, 29178642, 30576320, 31087526, 30559420, 31734136, 34327195, 32531858, 32865313, 29398085, 29518907, 33726816, 32037395, 31816670, 28619647, 28510626, 16909394, 25761237, 34196655, 30193310)

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 22, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CEP290: PM3:Very Strong, PVS1, PP1:Strong, PM2

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Leber congenital amaurosis 10 Pathogenic:4 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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.

Jul 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 30, 2021

Institute of Medical Molecular Genetics, University of Zurich

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 29, 2012

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

CEP290-related disorder Pathogenic:3

May 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CEP290 c.2991+1655A>G variant is predicted to interfere with splicing. This deep intronic 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 transcript (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.

Apr 25, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.027%). Predicted Consequence/Location: Intron variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 16909394). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001337 / PMID: 16909394). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Sep 16, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Retinal dystrophy Pathogenic:2

Jul 25, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 01, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joubert syndrome 5 Pathogenic:2

Oct 16, 2023

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PM3,PP3,PP4.

Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis Pathogenic:1

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 16909394, 23344081). For these reasons, this variant has been classified as Pathogenic.

Leber congenital amaurosis Pathogenic:1

Sep 23, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joubert syndrome 1 Pathogenic:1

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bardet-Biedl syndrome 14 Pathogenic:1

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intellectual disability Pathogenic:1

Aug 03, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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

Apr 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinitis pigmentosa Pathogenic:1

Sep 01, 2016

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	10
DANN	Benign	0.73
PhyloP100		0.041
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
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

Other links and lift over

dbSNP: rs281865192; hg19: chr12-88494960;