NM_025114.4:c.1665A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025114.4(CEP290):​c.1665A>T​(p.Lys555Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000254 in 1,575,632 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K555I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CEP290
NM_025114.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.171

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: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13582045).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CEP290NM_025114.4 linkc.1665A>T p.Lys555Asn missense_variant Exon 17 of 54 ENST00000552810.6 NP_079390.3 O15078Q05BJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CEP290ENST00000552810.6 linkc.1665A>T p.Lys555Asn missense_variant Exon 17 of 54 1 NM_025114.4 ENSP00000448012.1 O15078

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151910
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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
GnomAD2 exomes
AF:
0.00000553
AC:
1
AN:
180682
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.0000906
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000211
AC:
3
AN:
1423722
Hom.:
0
Cov.:
31
AF XY:
0.00000142
AC XY:
1
AN XY:
704728
show subpopulations
African (AFR)
AF:
0.0000917
AC:
3
AN:
32726
American (AMR)
AF:
0.00
AC:
0
AN:
38166
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25548
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38418
South Asian (SAS)
AF:
0.00
AC:
0
AN:
82202
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51246
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5714
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1090678
Other (OTH)
AF:
0.00
AC:
0
AN:
59024
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.408
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
AF:
0.00000658
AC:
1
AN:
151910
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74216
show subpopulations
African (AFR)
AF:
0.0000242
AC:
1
AN:
41384
American (AMR)
AF:
0.00
AC:
0
AN:
15238
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10538
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67944
Other (OTH)
AF:
0.00
AC:
0
AN:
2084
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
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:
0.0000712
Hom.:
0
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.000557
AC:
2
ESP6500EA
AF:
0.00
AC:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis Uncertain:1
Aug 31, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces lysine with asparagine at codon 555 of the CEP290 protein (p.Lys555Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 12, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.31
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.22
.;T;T;.
Eigen
Benign
-0.40
Eigen_PC
Benign
-0.36
FATHMM_MKL
Benign
0.51
D
LIST_S2
Uncertain
0.90
D;D;D;D
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.14
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.9
.;L;.;.
PhyloP100
-0.17
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.2
N;N;.;.
REVEL
Benign
0.11
Sift
Benign
0.10
T;T;.;.
Sift4G
Benign
0.30
T;T;T;T
Polyphen
0.59
.;P;.;.
Vest4
0.37
MutPred
0.15
.;Loss of ubiquitination at K555 (P = 0.0255);.;.;
MVP
0.72
MPC
0.12
ClinPred
0.34
T
GERP RS
-0.11
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.092
gMVP
0.31
Mutation Taster
=87/13
polymorphism

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: rs374824892; hg19: chr12-88512306; API