Variant rs758593134 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_025114.4(CEP290):c.180+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.00000421 in 1,426,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

CEP290
NM_025114.4 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.77

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 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.010349463 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-88140955-C-T is Pathogenic according to our data. Variant chr12-88140955-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 461777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88140955-C-T 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.180+1G>A		splice_donor_variant		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.180+1G>A		splice_donor_variant		1	NM_025114.4	ENSP00000448012	P4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000464

AC:

AN:

215658

Hom.:

AF XY:

0.00000856

AC XY:

AN XY:

116864

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000995

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000421

AC:

AN:

1426374

Hom.:

Cov.:

AF XY:

0.00000706

AC XY:

AN XY:

708044

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000547

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 09, 2020	- -
Likely pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2018

- -

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

Sep 22, 2023

This sequence change affects a donor splice site in intron 3 of the CEP290 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). This variant is present in population databases (rs758593134, gnomAD 0.001%). Disruption of this splice site has been observed in individual(s) with Leber congenital amaurosis (PMID: 16909394; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 461777). 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. -

Meckel syndrome, type 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Oct 18, 2021

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 18, 2021

- -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Jan 09, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.93

MutationTaster

Benign

1.0

D;D;D

GERP RS

5.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.97

Position offset: 1

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