rs386834158

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_025114.4(CEP290):​c.5493delA​(p.Ala1832ProfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,563,896 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CEP290
NM_025114.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:20

Conservation

PhyloP100: 2.39
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 12-88077789-CT-C is Pathogenic according to our data. Variant chr12-88077789-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 56739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88077789-CT-C is described in Lovd as [Pathogenic]. Variant chr12-88077789-CT-C is described in Lovd as [Likely_pathogenic]. Variant chr12-88077789-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CEP290NM_025114.4 linkc.5493delA p.Ala1832ProfsTer19 frameshift_variant Exon 40 of 54 ENST00000552810.6 NP_079390.3 O15078Q05BJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CEP290ENST00000552810.6 linkc.5493delA p.Ala1832ProfsTer19 frameshift_variant Exon 40 of 54 1 NM_025114.4 ENSP00000448012.1 O15078

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151748
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000224
AC:
5
AN:
223598
Hom.:
0
AF XY:
0.0000247
AC XY:
3
AN XY:
121346
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000489
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000149
AC:
21
AN:
1412148
Hom.:
0
Cov.:
27
AF XY:
0.0000128
AC XY:
9
AN XY:
702784
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000194
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151748
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74090
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:20
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:5
Jan 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

CEP290: PVS1, PM2, PM3 -

Sep 20, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Reported previously in association with CEP290-related disorders (PMID: 21245082, 19466712, 19764032); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34196655, 32531858, 34906470, 17564967, 17705300, 19466712, 19764032, 28041643, 31734136, 32581362, 31589614, 34426522, 35906228, 21245082, 36803942, 37224330) -

Aug 05, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

Feb 12, 2016
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Meckel syndrome, type 4 Pathogenic:3
-
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Dec 07, 2020
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.5493delA (p.Ala1832ProfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.2e-05 in 223598 control chromosomes. c.5493delA has been reported in the literature in individuals affected with Joubert syndromerelated disorders, retinal dystrophy, or Leber congenital amaurosis (Brancati_2007, Carss_2017, Feldhaus_2020). These data indicate that the variant may be associated with disease. Seven 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. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 01, 2008
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

CEP290-related disorder Pathogenic:2
May 13, 2022
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 05, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The CEP290 c.5493delA variant is predicted to result in a frameshift and premature protein termination (p.Ala1832Profs*19). This variant has been reported in individuals with Joubert Syndrome and related disorders (Brancati et al. 2007. PubMed ID: 17564967; Frank et al. 2008. PubMed ID: 17705300) or inherited retinal dystrophy (Carss et al. 2017. PubMed ID: 28041643, Patient G001347 in Supplemental Table S2). This variant is reported in 0.0049% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in CEP290 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Retinal dystrophy Pathogenic:2
Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Jan 01, 2021
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
Jul 09, 2019
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: PVS1,PM2,PP4,PP5. -

Apr 08, 2021
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was identified as compound heterozygous with NM_025114.4:c.2279_2280del. -

Leber congenital amaurosis 10 Pathogenic:1
Apr 08, 2021
Ocular Genomics Institute, Massachusetts Eye and Ear
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

The CEP290 c.5493del 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: PM2, PP1, PVS1. Based on this evidence we have classified this variant as Pathogenic. -

Leber congenital amaurosis Pathogenic:1
Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Polycystic kidney disease;C0266292:Abnormality of the kidney;C0431399:Familial aplasia of the vermis;C1840379:Cerebellar vermis hypoplasia;C1847762:Cerebellar cyst;C3275899:Hyperechogenic kidneys Pathogenic:1
Jan 29, 2014
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Bardet-Biedl syndrome 14 Pathogenic:1
Feb 29, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Pathogenic:1
Oct 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ala1832Profs*19) in the CEP290 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Leber congenital amaurosis and/or Meckel-Gruber syndrome (PMID: 17705300, 20683928, 21245082). This variant is also known as 5489_5493delA, c.5489del and p.Gln1830fs. ClinVar contains an entry for this variant (Variation ID: 56739). For these reasons, this variant has been classified as Pathogenic. -

Senior-Loken syndrome 6;C1857780:Joubert syndrome 5;C1857821:Leber congenital amaurosis 10;C1970161:Meckel syndrome, type 4 Pathogenic:1
Oct 08, 2021
New York Genome Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs386834158; hg19: chr12-88471566; API