rs776645403

Positions:

Variant summary

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

The NM_025114.4(CEP290):c.1078C>T(p.Arg360Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,307,728 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R360R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CEP290
NM_025114.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 1.34

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 12-88125357-G-A is Pathogenic according to our data. Variant chr12-88125357-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 530911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88125357-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4 linkuse as main transcript	c.1078C>T	p.Arg360Ter	stop_gained	13/54	ENST00000552810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6 linkuse as main transcript	c.1078C>T	p.Arg360Ter	stop_gained	13/54	1	NM_025114.4	P4

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151440

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000376

AC:

AN:

79762

Hom.:

AF XY:

0.0000231

AC XY:

AN XY:

43218

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000158

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000178

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000190

AC:

AN:

1156288

Hom.:

Cov.:

AF XY:

0.0000212

AC XY:

AN XY:

565940

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000616

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000359

Gnomad4 SAS exome

AF:

0.000227

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000118

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151440

Hom.:

Cov.:

AF XY:

0.0000406

AC XY:

AN XY:

73850

show subpopulations

Gnomad4 AFR

AF:

0.0000485

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:

0.0000295

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000111

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 06, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2021	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: 22355252, 25097241) -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CEP290 p.R360* variant was identified as a compound heterozygous variant in multiple individuals with Leber congenital amaurosis and retinitis pigmentosa (Yzer_2012_PMID: 22355252; Wang_2014_PMID: 25097241). The variant was identified in dbSNP (ID: rs776645403) and ClinVar (classified as pathogenic by Fulgent Genetics and Invitae). The variant was identified in control databases in 3 of 79762 chromosomes at a frequency of 0.00003761 (Genome Aggregation Database March 6, 2019, v2.1.1). The c.1078C>T variant leads to a premature stop codon at position 360 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the CEP290 gene are a mechanism of disease in the autosomal recessive conditions: Joubert syndrome, Leber congenital amaurosis, Meckel syndrome, Senior-Loken syndrome, and Bardet-Biedl syndrome. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Leber congenital amaurosis

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Bardet-Biedl syndrome 14

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 07, 2024

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

This sequence change creates a premature translational stop signal (p.Arg360*) 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 autosomal recessive Leber congenital amaurosis and autosomal recessive retinitis pigmentosa (PMID: 22355252, 25097241). ClinVar contains an entry for this variant (Variation ID: 530911). 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

Oct 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.80

MutationTaster

Benign

1.0

A;A;D

Vest4

0.94

GERP RS

3.4

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