rs137852832

Positions:

chr12-88077263-C-A

Variant summary

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

The ENST00000552810.6(CEP290):c.5668G>T(p.Gly1890Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,605,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G1890G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

CEP290
ENST00000552810.6 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:34O:1

Conservation

PhyloP100: 3.58

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:

LOC124902977 (HGNC:):

LOC124902977 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 12-88077263-C-A is Pathogenic according to our data. Variant chr12-88077263-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88077263-C-A is described in Lovd as [Pathogenic]. Variant chr12-88077263-C-A is described in Lovd as [Pathogenic]. Variant chr12-88077263-C-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.5668G>T	p.Gly1890Ter	stop_gained	41/54	ENST00000552810.6	NP_079390.3
LOC124902977	XR_007063393.1 linkuse as main transcript	n.887-5050C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6 linkuse as main transcript	c.5668G>T	p.Gly1890Ter	stop_gained	41/54	1	NM_025114.4	ENSP00000448012	P4

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151974

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000949

AC:

AN:

242464

Hom.:

AF XY:

0.000129

AC XY:

AN XY:

131646

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000203

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000154

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000143

AC:

208

AN:

1453284

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

101

AN XY:

722630

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000225

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000165

Gnomad4 OTH exome

AF:

0.0000833

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74356

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000103

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3472

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:34Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Joubert syndrome 5

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001333, PMID:16682973). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000095, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2007	- -
Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 01, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained p.G1890* in CEP290 (NM_025114.4) has been reported has been reported previously as homozygous and compound heterozygous in multiple individuals and is one of the most commonly reported variants in Joubert syndrome (Sayer et al,Bachmann-Gagescu R et al). This variant is predicted to cause loss of normal protein function through protein truncation. The G1890X variant is observed in 6/14472 (0.04%) alleles from individuals of South Asian background, in the ExAC dataset, and no individuals were reported to be homozygous. For these reasons, this variant has been classified as Pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Oct 19, 2023	This homozygous termination variant identified in 2 year male with GDD, and breathing difficulties with hypotonia, nystagmus, retinal dystrophy. MRI Brain revealed Molar Tooth sign suggestive of Joubert Syndrome. Family history of female sibling expired 10 hours of life with respiratory distress. This nucleotide change has an allele frequency of 0.0098% in gnomAD aggregate database [PM2], In-silico prediction tools [MutationTaster] predict a deleterious nature of this variant. This variant is submitted to clinvar database multiple times with an interpretation "Pathogenic/Likely Pathogenic". Clinvar variation id [1333] [PP5]. PMID [26092869] Based on the available evidences and the clinical phenotype in our case, this variant is classified as "Pathogenic". -
Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 03, 2023	This variant was identified as homozygous._x000D_ Criteria applied: PVS1, PM3_VSTR, PM2_SUP, PP4 -

not provided

Pathogenic:6Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2022	Nonsense 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: 25937446, 23591405, 23954617, 21866095, 25818971, 16682973, 22355252, 29518907, 29398085, 26092869, 30718709, 25525159, 32139166, 27353947, 16682970, 22693042, 29620724, 28559085, 31411728, 31734136, 31589614, 21245082, 21068128, 20690115, 17564967, 17345604, 16909394, 31091803, 31488071, 31346239, 30446612, 29298421, 30114557, 26862157, 26729329, 27081510, 23847139, 19778711) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 19, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
not provided, no classification provided	literature only	Retina International	-	- -

CEP290-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 13, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 26, 2024	The CEP290 c.5668G>T variant is predicted to result in premature protein termination (p.Gly1890). This variant is one of the most common pathogenic variants detected in CEP290 and has been documented as causative for Joubert syndrome (Sayer et al. 2006. PubMed ID: 16682973; Valente et al. 2006. PubMed ID: 16682970; Brancati et al. 2007. PubMed ID: 17564967; Bachmann-Gagescu et al. 2015. PubMed ID: 26092869). Different chain-terminating variants in CEP290 have been reported in patients with Meckel-Gruber syndrome (Baala et al. 2007. PubMed ID: 17564974; Frank et al. 2008. PubMed ID: 17705300) and Bardet-Biedl syndrome (Leitch et al. 2008. PubMed ID: 18327255). This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in CEP290 are expected to be pathogenic, and this variant has been classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1333/). Given all the evidence, we interpret c.5668G>T (p.Gly1890) as pathogenic. -

Leber congenital amaurosis 10

Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2024	PVS1,PM3(strong),PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 17, 2024	- -

Bardet-Biedl syndrome 14

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 28, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2020	- -

COG7 congenital disorder of glycosylation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Suma Genomics

- -

Leber congenital amaurosis

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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 25, 2024

This sequence change creates a premature translational stop signal (p.Gly1890*) 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 (rs137852832, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome, Leber congenital amaurosis, and/or retinitis pigmentosa (PMID: 16682970, 16682973, 17564967, 21068128, 21245082, 22355252, 22693042, 23591405, 23954617, 25818971, 26092869, 27353947). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1333). For these reasons, this variant has been classified as Pathogenic. -

Meckel-Gruber syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 22, 2013

- -

Meckel syndrome, type 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

- -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Senior-Loken syndrome 6;C1857780:Joubert syndrome 5

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Feb 01, 2019

- -

Senior-Loken syndrome 6;C1857780:Joubert syndrome 5;C1970161:Meckel syndrome, type 4;C2673874:Bardet-Biedl syndrome 14

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Suma Genomics

- -

Abnormality of the nervous system

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Meckel syndrome, type 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

- -

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

Apr 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.073

FATHMM_MKL

Benign

0.66

MutationTaster

Benign

1.0

A;A;A;A

Vest4

0.67

GERP RS

2.7

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