Variant 12-88136696-CTCTA-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_025114.4(CEP290):c.384_387del(p.Asp128GlufsTer34) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000979 in 1,613,522 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. D128D) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

CEP290
NM_025114.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 3.60

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:

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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 12-88136696-CTCTA-C is Pathogenic according to our data. Variant chr12-88136696-CTCTA-C is described in ClinVar as [Pathogenic]. Clinvar id is 56738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88136696-CTCTA-C is described in Lovd as [Pathogenic]. Variant chr12-88136696-CTCTA-C 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.384_387del	p.Asp128GlufsTer34	frameshift_variant	6/54	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.384_387del	p.Asp128GlufsTer34	frameshift_variant	6/54	1	NM_025114.4	ENSP00000448012	P4

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000562

AC:

AN:

249068

Hom.:

AF XY:

0.0000740

AC XY:

AN XY:

135118

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

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:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000999

AC:

146

AN:

1461408

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

727004

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000162

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000642

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CEP290-related disorder

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 04, 2018	The CEP290 c.384_387delTAGA (p.Asp128GlufsTer34) variant causes a frameshift and results in a premature truncation of the protein. The p.Asp128GlufsTer34 variant has been reported in four studies in which it is found in a total of seven individuals, including two homozygotes and five compound heterozygotes (Baala et al. 2007; Perrault et al. 2007; Aguilar et al. 2012; Sheck et al. 2018). Five of the individuals presented with brain abnormalities, including Dandy-Walker malformation, occipital meningocele, or cerebellar vermis hypoplasia, and were diagnosed with Meckel syndrome or Joubert syndrome upon fetal autopsy, while one 5-month old individual was reported to have normal development and was diagnosed with Leber congeital amaurosis upon clinical exam. The p.Asp128GlufsTer34variant was absent from 96 controls (Perrault et al. 2007) and is reported at a frequency of 0.01304 in the European American population of the Exome Sequencing Project. However, this frequency is orders of magnitude higher than the highest frequency reported in the Exome Aggregation Consortium, where the p.Asp128GlufsTer34 variant is found at a frequency of 0.00009 in the European (non-Finnish) population. Based on the potential impact of frameshift variant and collective clinical evidence, the p.Asp128GlufsTer34 variant is classified as pathogenic for CEP290-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 19, 2024	The CEP290 c.384_387delTAGA variant is predicted to result in a frameshift and premature protein termination (p.Asp128Glufs*34). This variant has been reported in the compound heterozygous state to be causative for Leber congenital amaurosis (Perrault et al. 2007. PubMed ID: 17345604) and Meckel syndrome (Vora et al. 2020. PubMed ID: 31974414). This variant is reported in 0.010% 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 01, 2024	Variant summary: CEP290 c.384_387delTAGA (p.Asp128GlufsX34) 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. The variant allele was found at a frequency of 5.6e-05 in 249068 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CEP290 causing CEP290-Related Disorders. c.384_387delTAGA has been reported in the literature in the presumed compound heterozygous and compound heterozygous states in at least 2 individuals affected with Leber congenital amaurosis or Joubert/Meckel spectrum disease (example, Areblom_2023, Aguilar_2012). The following publications have been ascertained in the context of this evaluation (PMID: 37510321, 23027964). ClinVar contains an entry for this variant (Variation ID: 56738). Based on the evidence outlined above, the variant was classified as pathogenic. -

Leber congenital amaurosis 10

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jul 05, 2020	- -

Meckel syndrome, type 4

Pathogenic:2

Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2007	- -

Spastic ataxia

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Jul 12, 2021

- -

Leber congenital amaurosis

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2022

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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23027964, 19466712, 29398085, 31974414, 21602930, 31589614, 32865313, 17564974, 17345604) -

Bardet-Biedl syndrome 14

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 30, 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

Jan 22, 2024

This sequence change creates a premature translational stop signal (p.Asp128Glufs*34) 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 (rs386834157, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Leber congenital amaurosis and Meckel syndrome (PMID: 17345604, 17564974, 21602930). It has also been observed to segregate with disease in related individuals. This variant is also known as 383_386delATAG. ClinVar contains an entry for this variant (Variation ID: 56738). 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

Sep 30, 2021

- -

Joubert syndrome 5

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Jun 28, 2016

The c.384_387delTAGA (p.Asp128Glufs*34) frameshift variant in the CEP290 gene has been previously reported in one family affected with Leber Congenital Amaurosis and two families affected with Meckel Syndrome (Baala et al., 2007; Perrault et al., 2007). In two unrelated individuals, this variant was observed in trans with other pathogenic variants (Cys998Ter, c.180+2T>A) (Baala et al., 2007; Perrault et al., 2007). This frameshift variant is predicted truncate the protein product, and loss of function variants, including variants downstream of this one, have been reported as a common mechanism of disease. This variant is reported at low frequency in the population databases (Exome Sequencing Project = NA; 1000 Genomes = NA; and ExAC = 0.009%). Therefore, this collective evidence supports the classification of the c.384_387delTAGA (p.Asp128Glufs*34) as a Pathogenic variant for Joubert Syndrome and Related Diseases. We have confirmed this finding in our laboratory using Sanger sequencing. -

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