rs534440681

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_025114.4(CEP290):​c.7311G>T​(p.Lys2437Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,581,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

CEP290
NM_025114.4 missense

Scores

2
8
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.472
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]
RLIG1 (HGNC:25322): (RNA 5'-phosphate and 3'-OH ligase 1) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.40770763).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CEP290NM_025114.4 linkc.7311G>T p.Lys2437Asn missense_variant 54/54 ENST00000552810.6 NP_079390.3 O15078Q05BJ6
RLIG1NM_001009894.3 linkc.*891C>A 3_prime_UTR_variant 7/7 ENST00000356891.4 NP_001009894.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CEP290ENST00000552810.6 linkc.7311G>T p.Lys2437Asn missense_variant 54/541 NM_025114.4 ENSP00000448012.1 O15078
C12orf29ENST00000356891.4 linkc.*891C>A 3_prime_UTR_variant 7/71 NM_001009894.3 ENSP00000349358.3 Q8N999-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151932
Hom.:
0
Cov.:
32
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:
0.000385
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
GnomAD3 exomes
AF:
0.00000821
AC:
2
AN:
243644
Hom.:
0
AF XY:
0.0000151
AC XY:
2
AN XY:
132168
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000112
Gnomad SAS 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:
0.00000769
AC:
11
AN:
1429514
Hom.:
0
Cov.:
26
AF XY:
0.0000126
AC XY:
9
AN XY:
712436
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000508
Gnomad4 SAS exome
AF:
0.0000120
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000644
Gnomad4 OTH exome
AF:
0.0000169
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152050
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000166
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

CEP290-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 22, 2024The CEP290 c.7311G>T variant is predicted to result in the amino acid substitution p.Lys2437Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Leber congenital amaurosis Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Oct 28, 2019- -
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 03, 2022This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 2437 of the CEP290 protein (p.Lys2437Asn). This variant is present in population databases (rs534440681, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. ClinVar contains an entry for this variant (Variation ID: 530915). 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: "Probably Damaging"; 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
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 23, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.54
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
.;.;T
Eigen
Benign
0.069
Eigen_PC
Benign
0.0026
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.87
D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.41
T;T;T
MetaSVM
Uncertain
-0.25
T
MutationAssessor
Uncertain
2.6
.;.;M
PrimateAI
Pathogenic
0.79
T
PROVEAN
Benign
-1.3
N;N;N
REVEL
Benign
0.20
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.010
D;D;D
Polyphen
1.0
.;.;D
Vest4
0.67
MutPred
0.18
.;.;Loss of methylation at K2437 (P = 0.0144);
MVP
0.78
MPC
0.37
ClinPred
0.78
D
GERP RS
0.56
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.48
gMVP
0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs534440681; hg19: chr12-88443090; API