Variant 12-88118527-ATT-ATTT 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.1666dupA(p.Ile556fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000588 in 1,475,626 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 0.000047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 0 hom. )

Consequence

CEP290
NM_025114.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

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:

CEP290 (HGNC:):

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 12-88118527-A-AT is Pathogenic according to our data. Variant chr12-88118527-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 217623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP290	NM_025114.4 linkuse as main transcript	c.1666dupA	p.Ile556fs	frameshift_variant	17/54	ENST00000552810.6	NP_079390.3	O15078Q05BJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6 linkuse as main transcript	c.1666dupA	p.Ile556fs	frameshift_variant	17/54	1	NM_025114.4	ENSP00000448012.1		O15078

Frequencies

GnomAD3 genomes

AF:

0.0000466

AC:

AN:

150316

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000665

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000650

AC:

861

AN:

1325310

Hom.:

Cov.:

AF XY:

0.000614

AC XY:

403

AN XY:

656742

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.000795

Gnomad4 ASJ exome

AF:

0.000671

Gnomad4 EAS exome

AF:

0.000390

Gnomad4 SAS exome

AF:

0.000785

Gnomad4 FIN exome

AF:

0.000791

Gnomad4 NFE exome

AF:

0.000629

Gnomad4 OTH exome

AF:

0.000601

GnomAD4 genome

AF:

0.0000466

AC:

AN:

150316

Hom.:

Cov.:

AF XY:

0.0000545

AC XY:

AN XY:

73346

show subpopulations

Gnomad4 AFR

AF:

0.000122

Gnomad4 AMR

AF:

0.0000665

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CEP290-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 08, 2024	The CEP290 c.1666dupA variant is predicted to result in a frameshift and premature protein termination (p.Ile556Asnfs*20). This variant has been reported in the compound heterozygous state in multiple individuals with a CEP290-associated disorder (for example see: Table 5, as c.1667_1668insA, Wang et al. 2013. PubMed ID: 23847139; Table S5, Bachmann-Gagescu et al. 2015. PubMed ID: 26092869; Table S1; Fleming LR et al. 2017. PubMed ID: 29146704). This variant is reported in 0.26% of alleles in individuals of South Asian 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	Sep 14, 2021	Variant summary: CEP290 c.1666dupA (p.Ile556AsnfsX20) 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 0.0018 in 158916 control chromosomes (gnomAD and publication data). c.1666dupA has been reported in the literature in individuals affected with Leber congenital amaurosis and Joubert syndrome(Wang_2013, Bachmann-Gagescu_2015, Fleming_2017, Xu_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Joubert syndrome 5

Pathogenic:2

Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	Aug 31, 2021	- -

Leber congenital amaurosis

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 15, 2020

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2020

- -

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

Mar 21, 2024

- -

Abnormality of prenatal development or birth

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

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 14, 2023

This sequence change creates a premature translational stop signal (p.Ile556Asnfs*20) 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 individual(s) with Leber congenital amaurosis or Joubert syndrome (PMID: 23847139, 26092869, 29146704). ClinVar contains an entry for this variant (Variation ID: 217623). For these reasons, this variant has been classified as Pathogenic. -

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