chr12-88131209-G-A

Variant names:

• chr12-88131209-G-A
• rs757641323
• NM_025114.4:c.451C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_025114.4(CEP290):​c.451C>T​(p.Arg151*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000295 in 1,493,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: CEP290 NM_025114.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 5.86
• Publications: 6 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 12-88131209-G-A is Pathogenic according to our data. Variant chr12-88131209-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.451C>T	p.Arg151*	stop_gained	Exon 7 of 54	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.451C>T	p.Arg151*	stop_gained	Exon 7 of 54	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000923 AC: 1 AN: 108296 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.0000203

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000313 AC: 42 AN: 1343956 Hom.: 0 Cov.: 29 AF XY: 0.0000317 AC XY: 21 AN XY: 662596

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27256

American (AMR) AF: 0.00 AC: 0 AN: 23408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22966

East Asian (EAS) AF: 0.0000301 AC: 1 AN: 33248

South Asian (SAS) AF: 0.00 AC: 0 AN: 66870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5330

European-Non Finnish (NFE) AF: 0.0000377 AC: 40 AN: 1060322

Other (OTH) AF: 0.0000180 AC: 1 AN: 55478

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 149064 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 1 AN XY: 72482

African (AFR) AF: 0.00 AC: 0 AN: 40448

American (AMR) AF: 0.00 AC: 0 AN: 15008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67554

Other (OTH) AF: 0.00 AC: 0 AN: 2032

Alfa AF: 0.0000301 Hom.: 0

ExAC AF: 0.00000874 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 11, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R151X variant in the CEP290 gene has been reported previously in association with Leber congenital amaurosis, early-onset severe retinal dystrophy, and a nonspecified retinal dystrophy (Littink et al., 2010; Huang et al., 2015). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R151X variant was not observed in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on currently available evidence, we interpret R151X as a pathogenic variant. -

not specified Pathogenic:1

Jul 09, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CEP290 c.451C>T;p.Arg151Ter variant has been described in at least one individual with retinal dystrophy (Huang 2015) and one family with early onset severe retinal dystrophy and Leber congential amaurosis (Littink 2010). The variant is listed in the ClinVar database (Variation ID: 372761) and the dbSNP variant database (rs757641323) but is not listed in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The variant introduces a premature termination codon, but at least one report shows that this variant leads to a skipping of exon 7 or exon 7 and 8, which leads to an in-frame product lacking a portion of a functional domain. Considering available information, this variant is classified as likely pathogenic. References: Huang XF et al. Genotype-phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing. Genet Med. 2015 Apr;17(4):271-8. Littink KW et al. A novel nonsense mutation in CEP290 induces exon skipping and leads to a relatively mild retinal phenotype. Invest Ophthalmol Vis Sci. 2010 Jul;51(7):3646-52. -

Inborn genetic diseases Pathogenic:1

Mar 20, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.451C>T (p.R151*) alteration, located in exon 7 (coding exon 6) of the CEP290 gene, consists of a C to T substitution at nucleotide position 451. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 151. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.001% (1/108296) total alleles studied. The highest observed frequency was 0.002% (1/49182) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and/or in conjunction with other variant(s) in this same gene in individual(s) with features consistent with Leber congenital amaurosis and segregated with disease in at least one family (Huang, 2015; Roosing, 2017; Littink, 2010; external communication). RNA studies have demonstrated that this alteration results in transcripts predicted to lead to protein products with in-frame deletions of 18 or 25 amino acid(s); however, the exact functional impact of the deleted amino acid(s) is unknown at this time (Littink, 2010). Based on the available evidence, this alteration is classified as pathogenic. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis Pathogenic:1

Oct 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg151*) in the CEP290 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with retinal dystrophy (PMID: 20130272, 25356976, 28829391; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372761). Studies have shown that this premature translational stop signal results in skipping of exon 7 or exons 7-8, but is expected to preserve the integrity of the reading-frame (PMID: 20130272). For these reasons, this variant has been classified as Pathogenic. -

Leber congenital amaurosis 10 Pathogenic:1

Sep 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome 5 (MIM#610188), Leber congenital amaurosis 10 (MIM#611755), Meckel syndrome 4 (MIM#611134) and Senior-Loken syndrome 6 (MIM#610189). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR experiments using patient cDNA have demonstrated that this variant results in in-frame skipping of either exon 7 (p.(Leu148_Glu165del)) or exon 7 and exon 8 (p.(Leu148_Lys172del)) (PMIDs: 20130272, 28829391). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 1 heterozygote, 0 homozygotes). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by multiple clinical diagnostic laboratories and has been reported as compound heterozygous in multiple individuals with Leber congenital amaurosis, early-onset severe retinal dystrophy or oligocone trichromacy (PMIDs: 20130272, 28829391, 25356976, 27208204). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_025114.3(CEP290):c.2506G>T; p.(Glu836*)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation testing). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Bardet-Biedl syndrome 14 Pathogenic:1

Feb 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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 Pathogenic:1

May 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.9
Vest4		0.82
GERP RS		5.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.33		Position offset: 9

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

Other links and lift over

dbSNP: rs757641323; hg19: chr12-88524986;