12-88118527-ATT-AT

Position:

chr12-88118527-ATT-AT

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]

CEP290 links:

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 12-88118527-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
CEP290	NM_025114.4 linkuse as main transcript	c.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
CEP290	ENST00000552810.6 linkuse as main transcript	c.1666del	p.Ile556PhefsTer17	frameshift_variant	17/54	1	NM_025114.4	ENSP00000448012	P4

Frequencies

GnomAD3 genomes

AF:

0.0000532

AC:

AN:

150322

Hom.:

Cov.:

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.:

Cov.:

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:

AN:

150422

Hom.:

Cov.:

AF XY:

0.0000408

AC XY:

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:

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 submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2023	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; 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 submitter	clinical testing	Revvity Omics, Revvity	Jan 02, 2022	- -

Leber congenital amaurosis

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -

Leber congenital amaurosis 10

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Aug 03, 2021	This 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 submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The 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 submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 29, 2017	- -

Joubert syndrome 5

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Oct 13, 2024	This 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 submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -

CEP290-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2024

The 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 submitter

clinical testing

Mendelics

May 28, 2019

- -

Bardet-Biedl syndrome 14

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2024

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

This 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 submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over