chr12-88118527-AT-A

Variant summary

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

The ENST00000552810.6(CEP290):​c.1666del​(p.Ile556PhefsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,502,300 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. I556I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CEP290
ENST00000552810.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 2.81
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]

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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 12-88118527-AT-A is Pathogenic according to our data. Variant chr12-88118527-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 217622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88118527-AT-A is described in Lovd as [Likely_pathogenic]. Variant chr12-88118527-AT-A is described in Lovd as [Pathogenic]. Variant chr12-88118527-AT-A is described in Lovd as [Pathogenic]. Variant chr12-88118527-AT-A is described in Lovd as [Pathogenic]. Variant chr12-88118527-AT-A is described in Lovd as [Likely_pathogenic]. Variant chr12-88118527-AT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CEP290NM_025114.4 linkuse as main transcriptc.1666del p.Ile556PhefsTer17 frameshift_variant 17/54 ENST00000552810.6 NP_079390.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CEP290ENST00000552810.6 linkuse as main transcriptc.1666del p.Ile556PhefsTer17 frameshift_variant 17/541 NM_025114.4 ENSP00000448012 P4

Frequencies

GnomAD3 genomes
AF:
0.0000532
AC:
8
AN:
150322
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000733
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:
0.0000741
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.000173
AC:
234
AN:
1351878
Hom.:
0
Cov.:
31
AF XY:
0.000188
AC XY:
126
AN XY:
669516
show subpopulations
Gnomad4 AFR exome
AF:
0.000354
Gnomad4 AMR exome
AF:
0.000476
Gnomad4 ASJ exome
AF:
0.0000826
Gnomad4 EAS exome
AF:
0.000521
Gnomad4 SAS exome
AF:
0.000270
Gnomad4 FIN exome
AF:
0.000308
Gnomad4 NFE exome
AF:
0.000134
Gnomad4 OTH exome
AF:
0.000161
GnomAD4 genome
AF:
0.0000532
AC:
8
AN:
150422
Hom.:
0
Cov.:
32
AF XY:
0.0000408
AC XY:
3
AN XY:
73466
show subpopulations
Gnomad4 AFR
AF:
0.0000731
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:
0.0000741
Gnomad4 OTH
AF:
0.00
Asia WGS
AF:
0.00145
AC:
5
AN:
3474

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 12, 2023Frameshift 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; This variant is associated with the following publications: (PMID: 31589614, 21228398, 17564967, 27491411, 26047050, 29641573, 26092869, 32165824, 35627109, 29771326, 31630094, 36460718, 34906470, 36729443, 32507488, 33970760, 31087526, 36819107, 33576794, 32865313, 34196655) -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJan 02, 2022- -
Leber congenital amaurosis Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, no assertion criteria providedresearchSharon lab, Hadassah-Hebrew University Medical CenterJun 23, 2019- -
Leber congenital amaurosis 10 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingBreakthrough Genomics, Breakthrough GenomicsAug 03, 2021This variant was previously reported in individuals with Joubert syndrome and observed to segregate with disease in related individuals [PMID: 26047050, 26092869, 27491411]. Loss-of-function variants in the CEP290 gene are reported to be pathogenic [PMID: 16909394, 17345604, 20690115]. -
Pathogenic, criteria provided, single submitterresearchOcular Genomics Institute, Massachusetts Eye and EarApr 08, 2021The CEP290 c.1666del 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, PS3. Based on this evidence we have classified this variant as Pathogenic. -
Retinal dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Univ. Regensburg, Univ. RegensburgJan 01, 2018- -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsDec 29, 2017- -
Joubert syndrome 5 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterOct 13, 2024This sequence change creates a premature translational stop signal (GRCh38; NM_025114.4:c.1666del:p.Ile556PhefsTer17) in the CEP290 protein. This alteration is expected to result in loss of function by premature termination codon resulting in protein truncation, or nonsense-mediated mRNA decay. This alteration is interpreted as disease-causing mutation, a commonly known mechanism for disease. Well-established in-vitro or in-vivo functional studies supportive of a damaging effect on the gene or gene product PMID: 29771326 ClinVar contains an entry for this variant (Variation ID: 217622). This variant is associated with the following publications: PubMed: 26047050, 17564967, 26092869, 29771326, 27491411 In summary, this variant meets our criteria for classification as pathogenic based on the evidence outlined. -
Pathogenic, criteria provided, single submitterresearchUW Hindbrain Malformation Research Program, University of WashingtonFeb 23, 2015- -
CEP290-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 15, 2024The CEP290 c.1666delA variant is predicted to result in a frameshift and premature protein termination (p.Ile556Phefs*17). This variant in the homozygous or compound heterozygous state has been reported to be causative for CEP290-related disorders (Brancati et al. 2007. PubMed ID: 17564967; Wang et al. 2015. PubMed ID: 26047050; Zhu et al. 2021. PubMed ID: 33970760). This variant had been reported in 0.18% of alleles in individuals of European (Non-Finnish) descent in gnomAD 2.1.1 (as displayed in the table above). However, due to technical limitations, these numbers were not reliable. With a higher quality data in gnomAD V4 dataset, this variant has been identified at a maximum frequency of 0.0457% of alleles in individuals of South Asian descent. Frameshift variants in CEP290 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Joubert syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Bardet-Biedl syndrome 14 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 23, 2024- -
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 30, 2023This sequence change creates a premature translational stop signal (p.Ile556Phefs*17) 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 Joubert syndrome (PMID: 26047050, 26092869, 27491411). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217622). 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;C2673874:Bardet-Biedl syndrome 14 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 19, 2021- -

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: rs727503855; hg19: chr12-88512304; API