rs781670422

Variant summary

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

The NM_025114.4(CEP290):c.2390del(p.Lys797SerfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 1,331,726 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 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CEP290
NM_025114.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12U:1

Conservation

PhyloP100: 0.685

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 12-88109158-CT-C is Pathogenic according to our data. Variant chr12-88109158-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 438223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88109158-CT-C is described in Lovd as [Likely_pathogenic]. Variant chr12-88109158-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4 linkuse as main transcript	c.2390del	p.Lys797SerfsTer2	frameshift_variant	23/54	ENST00000552810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6 linkuse as main transcript	c.2390del	p.Lys797SerfsTer2	frameshift_variant	23/54	1	NM_025114.4	P4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151820

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000493

AC:

AN:

121668

Hom.:

AF XY:

0.0000746

AC XY:

AN XY:

66986

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000120

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:

0.0000524

Gnomad OTH exome

AF:

0.000350

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1179906

Hom.:

Cov.:

AF XY:

0.0000237

AC XY:

AN XY:

590396

show subpopulations

Gnomad4 AFR exome

AF:

0.000166

Gnomad4 AMR exome

AF:

0.0000541

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:

0.0000153

Gnomad4 OTH exome

AF:

0.0000401

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151820

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74122

show subpopulations

Gnomad4 AFR

AF:

0.0000968

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2021	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: 28041643, 29343940, 21245082, 29844330) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Joubert syndrome 5

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift variant c.2390del (p.Lys797SerfsTer2) in CEP290 gene has been observed in several individuals affected with CEP290-related conditions(Bryant L et.al.,2017). This variant has been reported to the ClinVar database as Pathogenic. The p.Lys797SerfsTer2 variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.004931% is reported in gnomAD. This variant causes a frameshift starting with codon Lysine 797, changes this amino acid to Serine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Lys797SerfsTer2. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

Leber congenital amaurosis

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 06, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 29, 2024	The p.Lys797SerfsX2 variant in CEP290 has been reported in at least 2 individuals with Leber congenital amaurosis: in 1 homozygote and 1 compound heterozygote with another disease-causing variant in CEP290 (Bryant 2018 PMID: 29343940, Hosono 2018 PMID: 29844330). It has also been identified in the heterozygous state in 1 individual with retinal disease. This variant has been reported by other clinical laboratories in ClinVar (Variation ID 438223) and has been identified in 0.01% (4/41328) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This is consistent with the prevalence of the disease in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 797 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the CEP290 gene is an established disease mechanism in autosomal recessive CEP290-related ciliopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive CEP290-related ciliopathy. ACMG/AMP Criteria applied: PVS1, PM3, PM2_Supporting. -

CEP290-related condition

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2024

The CEP290 c.2390delA variant is predicted to result in a frameshift and premature protein termination (p.Lys797Serfs*2). This variant has been reported in homozygous and compound heterozygous states in patients with Leber congenital amaurosis (LCA) and other retinal degeneration disorders (Bryant et al. 2018. PubMed ID: 29343940; Hosono et al. 2018. PubMed ID: 29844330). This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD. Frameshift variants in CEP290 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Bardet-Biedl syndrome 14

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 13, 2023

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 14, 2023

This sequence change creates a premature translational stop signal (p.Lys797Serfs*2) 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). This variant is present in population databases (rs781670422, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with CEP290-related conditions (PMID: 29343940, 29844330). ClinVar contains an entry for this variant (Variation ID: 438223). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

Feb 17, 2022

- -

Retinitis pigmentosa

Uncertain:1

Uncertain significance, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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