NM_025114.4:c.4237G>C
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_025114.4(CEP290):āc.4237G>Cā(p.Asp1413His) variant causes a missense change. The variant allele was found at a frequency of 0.00255 in 1,600,388 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. D1413E) has been classified as Uncertain significance.
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: Benign. The variant received -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00187 AC: 285AN: 152064Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00232 AC: 531AN: 229244 AF XY: 0.00230 show subpopulations
GnomAD4 exome AF: 0.00262 AC: 3788AN: 1448206Hom.: 9 Cov.: 30 AF XY: 0.00257 AC XY: 1848AN XY: 718986 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00188 AC: 286AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.00203 AC XY: 151AN XY: 74412 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:2
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Variant summary: CEP290 c.4237G>C (p.Asp1413His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 229244 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 2.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in CEP290 causing Meckel Syndrome Type 4 phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no penetrant association of c.4237G>C in individuals affected with Meckel Syndrome Type 4 and no experimental evidence demonstrating its impact on protein function have been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus as likely benign/benign (n=6) (VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign. -
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not provided Benign:3
CEP290: BP4, BS2 -
This variant is associated with the following publications: (PMID: 28127548, 27166760) -
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Meckel syndrome, type 4 Uncertain:2
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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Senior-Loken syndrome 6 Uncertain:1Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
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Bardet-Biedl syndrome 14 Uncertain:1Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
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Joubert syndrome 5 Uncertain:1Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
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Leber congenital amaurosis 10 Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
CEP290-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis Benign:1
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Leber congenital amaurosis Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at