GeneBe

rs1555225566

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_025114.4(CEP290):​c.825_828delAAAA​(p.Glu277ThrfsTer15) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000771 in 1,297,382 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

CEP290
NM_025114.4 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.08

Publications

0 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 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;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CEP290NM_025114.4 linkc.825_828delAAAA p.Glu277ThrfsTer15 frameshift_variant Exon 10 of 54 ENST00000552810.6 NP_079390.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CEP290ENST00000552810.6 linkc.825_828delAAAA p.Glu277ThrfsTer15 frameshift_variant Exon 10 of 54 1 NM_025114.4 ENSP00000448012.1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.71e-7
AC:
1
AN:
1297382
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
642670
show subpopulations
African (AFR)
AF:
0.0000376
AC:
1
AN:
26592
American (AMR)
AF:
0.00
AC:
0
AN:
25654
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23452
East Asian (EAS)
AF:
0.00
AC:
0
AN:
31760
South Asian (SAS)
AF:
0.00
AC:
0
AN:
70668
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
48424
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5368
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1011556
Other (OTH)
AF:
0.00
AC:
0
AN:
53908
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
7.1

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

Other links and lift over

dbSNP: rs1555225566; hg19: chr12-88523494; API