chr12-88120162-T-A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_025114.4(CEP290):​c.1474A>T​(p.Lys492*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000013 in 1,540,382 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 (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

CEP290
NM_025114.4 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.45

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 12 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 12-88120162-T-A is Pathogenic according to our data. Variant chr12-88120162-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 461774.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CEP290NM_025114.4 linkc.1474A>T p.Lys492* stop_gained Exon 15 of 54 ENST00000552810.6 NP_079390.3 O15078Q05BJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CEP290ENST00000552810.6 linkc.1474A>T p.Lys492* stop_gained Exon 15 of 54 1 NM_025114.4 ENSP00000448012.1 O15078

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
32
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
7.20e-7
AC:
1
AN:
1388170
Hom.:
0
Cov.:
27
AF XY:
0.00000146
AC XY:
1
AN XY:
684930
show subpopulations
African (AFR)
AF:
0.0000319
AC:
1
AN:
31370
American (AMR)
AF:
0.00
AC:
0
AN:
35238
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25076
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36152
South Asian (SAS)
AF:
0.00
AC:
0
AN:
74680
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49510
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5566
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1073084
Other (OTH)
AF:
0.00
AC:
0
AN:
57494
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74354
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41444
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5204
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68042
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.725
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis Pathogenic:1
Mar 29, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 461774). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys492*) 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). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.62
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Uncertain
0.96
D
PhyloP100
5.5
Vest4
0.87
GERP RS
5.7
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1278679056; hg19: chr12-88513939; API