rs1159836808

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_025114.4(CEP290):c.7397T>C(p.Phe2466Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000561 in 1,604,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. F2466Y) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CEP290
NM_025114.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:3

Conservation

PhyloP100: -2.50

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 links:

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]

RLIG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025745839).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4 link	c.7397T>C	p.Phe2466Ser	missense_variant	Exon 54 of 54	ENST00000552810.6	NP_079390.3	O15078Q05BJ6
RLIG1	NM_001009894.3 link	c.*805A>G		3_prime_UTR_variant	Exon 7 of 7	ENST00000356891.4	NP_001009894.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6 link	c.7397T>C	p.Phe2466Ser	missense_variant	Exon 54 of 54	1	NM_025114.4	ENSP00000448012.1		O15078
RLIG1	ENST00000356891.4 link	c.*805A>G		3_prime_UTR_variant	Exon 7 of 7	1	NM_001009894.3	ENSP00000349358.3		Q8N999-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000415

AC:

AN:

241128

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000300

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:

0.00000482

AC:

AN:

1452522

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

721818

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33086

American (AMR)

AF:

0.0000459

AC:

AN:

43620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25938

East Asian (EAS)

AF:

0.00

AC:

AN:

39484

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83070

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4190

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1109826

Other (OTH)

AF:

0.0000167

AC:

AN:

59966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.0000656

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67894

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis

Uncertain:1

Sep 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2466 of the CEP290 protein (p.Phe2466Ser). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 946983). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -

CEP290-related disorder

Uncertain:1

Jul 30, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CEP290 c.7397T>C variant is predicted to result in the amino acid substitution p.Phe2466Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0030% of alleles in individuals of Latino 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

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.8

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.080

.;.;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.44

T;T;T

M_CAP

Benign

0.0062

MetaRNN

Benign

0.026

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

.;.;N

PhyloP100

-2.5

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.10

N;N;N

REVEL

Benign

0.041

Sift

Benign

0.65

T;T;T

Sift4G

Benign

0.65

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.22

MVP

0.32

MPC

0.084

ClinPred

0.024

GERP RS

-9.5

Varity_R

0.032

gMVP

0.31

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over