rs747835249

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_025114.4(CEP290):c.2052+1_2052+2delGT variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000442 in 1,537,196 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

CEP290
NM_025114.4 splice_donor, intron

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.52

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

CEP290-related ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Joubert syndrome 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Bardet-Biedl syndrome 14
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis 10
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome with oculorenal defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Senior-Loken syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CEP290 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PP5

Variant 12-88114417-TAC-T is Pathogenic according to our data. Variant chr12-88114417-TAC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 236466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4 link	c.2052+1_2052+2delGT		splice_donor_variant, intron_variant	Intron 20 of 53	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6 link	c.2052+1_2052+2delGT		splice_donor_variant, intron_variant	Intron 20 of 53	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000205

AC:

AN:

146660

AF XY:

0.0000259

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000511

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000484

AC:

AN:

1385056

Hom.:

AF XY:

0.0000410

AC XY:

AN XY:

682894

show subpopulations

African (AFR)

AF:

0.0000326

AC:

AN:

30674

American (AMR)

AF:

0.00

AC:

AN:

32306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24776

East Asian (EAS)

AF:

0.00

AC:

AN:

35312

South Asian (SAS)

AF:

0.00

AC:

AN:

76082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48746

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.0000540

AC:

AN:

1074094

Other (OTH)

AF:

0.000139

AC:

AN:

57452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Nov 22, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 27535533, 23847139, 32865313) -

Jun 05, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Pathogenic:2

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 11, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis

Pathogenic:1

Jun 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a splice site in intron 20 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 (rs747835249, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with Leber congenital amaurosis (LCA) (PMID: 23847139, 28510626, 28660274). ClinVar contains an entry for this variant (Variation ID: 236466). 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. -

CEP290-related disorder

Pathogenic:1

Apr 15, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CEP290 c.2052+1_2052+2delGT variant is predicted to result in a deletion affecting a canonical splice site. This variant was reported along with a second pathogenic variant in individuals with non-syndromic Leber congenital amaurosis and in one patient with Joubert syndrome (Wang et al. 2013. PubMed ID: 23847139; Sallum et al. 2020. PubMed ID: 32865313). This variant is reported in 0.0051% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt splicing in CEP290 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Leber congenital amaurosis

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Bardet-Biedl syndrome 14

Pathogenic:1

Mar 07, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Jun 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.5

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.97

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over