NM_025114.4:c.2551G>A
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B.
The NM_025114.4(CEP290):c.2551G>A(p.Val851Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000244 in 1,555,130 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).
Frequency
Consequence
NM_025114.4 missense
Scores
Clinical Significance
Conservation
Publications
- CEP290-related ciliopathyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- Joubert syndrome 5Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
- Bardet-Biedl syndrome 14Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- Leber congenital amaurosis 10Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- Leber congenital amaurosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Bardet-Biedl syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Joubert syndrome with oculorenal defectInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Meckel syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Senior-Loken syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152076Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000104 AC: 18AN: 173102 AF XY: 0.0000435 show subpopulations
GnomAD4 exome AF: 0.0000257 AC: 36AN: 1403054Hom.: 0 Cov.: 29 AF XY: 0.0000159 AC XY: 11AN XY: 693420 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74292 show subpopulations
ClinVar
Submissions by phenotype
CEP290-related disorder Uncertain:2
no criteria met -
The CEP290 c.2551G>A variant is predicted to result in the amino acid substitution p.Val851Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.075% of alleles in individuals of Latino descent in gnomAD, which may be too frequent to be an unreported primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis Uncertain:1
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 851 of the CEP290 protein (p.Val851Ile). This variant is present in population databases (rs764963626, gnomAD 0.07%). 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: 241583). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CEP290 protein function with a negative predictive value of 80%. 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. -
Leber congenital amaurosis Uncertain:1
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Senior-Loken syndrome 6;C1857780:Joubert syndrome 5;C1857821:Leber congenital amaurosis 10;C1970161:Meckel syndrome, type 4 Uncertain:1
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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
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Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not provided Benign:1
See Variant Classification Assertion Criteria. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at