rs758550675

chr12-88140968-CTGAG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_025114.4(CEP290):c.164_167del(p.Thr55SerfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000126 in 1,588,116 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T55T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CEP290 NM_025114.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.32

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-88140968-CTGAG-C is Pathogenic according to our data. Variant chr12-88140968-CTGAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 217624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88140968-CTGAG-C is described in Lovd as [Pathogenic]. Variant chr12-88140968-CTGAG-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4	c.164_167del	p.Thr55SerfsTer3	frameshift_variant	3/54	ENST00000552810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6	c.164_167del	p.Thr55SerfsTer3	frameshift_variant	3/54	1	NM_025114.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152112 Hom.: 0 Cov.: 33

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000179 AC: 4 AN: 223432 Hom.: 0 AF XY: 0.0000248 AC XY: 3 AN XY: 120952

Gnomad AFR exome AF: 0.0000713

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000620

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 17 AN: 1435890 Hom.: 0 AF XY: 0.0000140 AC XY: 10 AN XY: 712740

Gnomad4 AFR exome AF: 0.0000924

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000907

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74426

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 20, 2024	The p.Thr55SerfsX3 variant in CEP290 has been reported in the compound heterozygous state in at least 7 individuals with CEP290-associated disorders (Bachmann-Gagescu 2015 PMID: 26092869, Schueler 2016 PMID: 26673778, Yohe 2020 PMID: 31816670, Sallum 2020 PMID: 32865313, Areblom 2023 PMID: 37510321, Li 2023 PMID: 36729443, Wang 2023 PMID: 36990420). It at least 5 individuals, this variant was reported with another disease-causing variant in CEP290, and the variants have been confirmed in trans in at least one individual. This variant segregated with disease in 1 affected relative from 1 family (Sallum 2020 PMID: 32865313). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 217624) and has been identified in 0.01% (1/5956) of Middle Eastern and 0.004% (3/74020) African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v4.0.0). This is consistent with the prevalence of the disease in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 55 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the CEP290 gene is an established disease mechanism in autosomal recessive CEP290-related ciliopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive CEP290-related ciliopathy. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting, PP1. -

Bardet-Biedl syndrome 14 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 30, 2022	The CEP290 c.164_167del variant is classified as a PATHOGENIC variant (PVS1, PM2, PS4_supporting) The variant is a 4-base pair deletion in exon 3/54 of the CEP290 gene which results in a frameshift starting at codon Threonine 55, changes this amino acid to an Serine, and creating a premature STOP codon 3 amino acids downstream (denoted p.Thr55Serfs*3) (PVS1). The variant has been reported in dbSNP (rs758550675) but is rare in the disease databases (gnomAD: 3/152112, 0 homozygote) (PM2). The variant has been reported in both ClinVar (ID: #217624) and HGMD (accession: CD075347) as a disease causing variant (PS4_supporting). -

Joubert syndrome 5 Pathogenic:2

Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2022

The c.164_167delCTCA (p.T55Sfs*3) alteration, located in exon 3 (coding exon 2) of the CEP290 gene, consists of a deletion of 4 nucleotides from position 164 to 167, causing a translational frameshift with a predicted alternate stop codon after 3 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in conjunction with other pathogenic CEP290 mutations in multiple individuals with CEP290-related ciliopathies, including Leber congenital amaurosis (Bachmann-Gagescu, 2015; Schueler, 2016; Yohe, 2020; Sallum, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 10, 2023

This sequence change creates a premature translational stop signal (p.Thr55Serfs*3) in the CEP290 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). This variant is present in population databases (rs758550675, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome (PMID: 17617513, 26092869). ClinVar contains an entry for this variant (Variation ID: 217624). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.35		Position offset: -12

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

Publications

LitVar

Other links and lift over

dbSNP: rs758550675; hg19: chr12-88534745;