rs773578133

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_025114.4(CEP290):​c.1199C>T​(p.Thr400Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,459,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T400A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CEP290
NM_025114.4 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 2.85

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.07089952).
BP6
Variant 12-88121157-G-A is Benign according to our data. Variant chr12-88121157-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461773.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CEP290NM_025114.4 linkc.1199C>T p.Thr400Ile missense_variant Exon 14 of 54 ENST00000552810.6 NP_079390.3 O15078Q05BJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CEP290ENST00000552810.6 linkc.1199C>T p.Thr400Ile missense_variant Exon 14 of 54 1 NM_025114.4 ENSP00000448012.1 O15078

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000689
AC:
17
AN:
246646
AF XY:
0.0000374
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000502
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1459358
Hom.:
0
Cov.:
31
AF XY:
0.00000964
AC XY:
7
AN XY:
725912
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33324
American (AMR)
AF:
0.000384
AC:
17
AN:
44322
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26086
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39634
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85772
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53160
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111022
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60274
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
1
3
4
6
7
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
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000662
AC:
8

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

CEP290-related disorder Uncertain:1
Mar 20, 2024
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

The CEP290 c.1199C>T variant is predicted to result in the amino acid substitution p.Thr400Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.050% of alleles in individuals of Latino descent in gnomAD, which is likely too common for a primary cause of disease. Although we suspect this variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis Uncertain:1
Sep 27, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 400 of the CEP290 protein (p.Thr400Ile). This variant is present in population databases (rs773578133, gnomAD 0.05%). This missense change has been observed in individuals with CEP290-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 461773). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CEP290 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Senior-Loken syndrome 6;C1857780:Joubert syndrome 5;C1857821:Leber congenital amaurosis 10;C1970161:Meckel syndrome, type 4;C2673874:Bardet-Biedl syndrome 14 Uncertain:1
Jan 09, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
Apr 27, 2018
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.091
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.14
.;T;T;.
Eigen
Benign
-0.35
Eigen_PC
Benign
-0.22
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.64
T;T;T;T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.071
T;T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.41
.;N;.;.
PhyloP100
2.8
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.1
N;N;.;.
REVEL
Benign
0.041
Sift
Uncertain
0.0090
D;D;.;.
Sift4G
Benign
0.070
T;T;T;T
Polyphen
0.0010
.;B;.;.
Vest4
0.23
MutPred
0.16
Gain of catalytic residue at S402 (P = 0.0698);Gain of catalytic residue at S402 (P = 0.0698);.;Gain of catalytic residue at S402 (P = 0.0698);
MVP
0.68
MPC
0.055
ClinPred
0.050
T
GERP RS
4.0
Varity_R
0.056
gMVP
0.11
Mutation Taster
=84/16
polymorphism

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: rs773578133; hg19: chr12-88514934; API