12-88055666-AT-ATT

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.6869_6870insA(p.Asn2290LysfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,401,328 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. N2290N) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: CEP290 NM_025114.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.64

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]

LOC124902977 (HGNC:):

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 12-88055666-A-AT is Pathogenic according to our data. Variant chr12-88055666-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 156386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4	c.6869_6870insA	p.Asn2290LysfsTer6	frameshift_variant	50/54	ENST00000552810.6
LOC124902977	XR_007063393.1	n.772+402dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6	c.6869_6870insA	p.Asn2290LysfsTer6	frameshift_variant	50/54	1	NM_025114.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000621 AC: 87 AN: 1401328 Hom.: 0 Cov.: 29 AF XY: 0.0000895 AC XY: 62 AN XY: 692712

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.000205

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.0000527

Gnomad4 SAS exome AF: 0.000658

Gnomad4 FIN exome AF: 0.0000197

Gnomad4 NFE exome AF: 0.0000185

Gnomad4 OTH exome AF: 0.0000343

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CEP290-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 30, 2022

Variant summary: CEP290 c.6869dupA (p.Asn2290LysfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00027 in 161872 control chromosomes. c.6869dupA has been reported in the literature in individuals affected with CEP290-Related Disorders. These data indicate that the variant may be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Leber congenital amaurosis 10 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Diagnostics Laboratory, Seoul National University Hospital

Sep 18, 2014

- -

Leber congenital amaurosis Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Bardet-Biedl syndrome 14 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 16, 2023

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

This sequence change creates a premature translational stop signal (p.Asn2290Lysfs*6) 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). 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 individual(s) with Leber congenital amaurosis (PMID: 25445212). This variant is also known as c.6869_6870insA. ClinVar contains an entry for this variant (Variation ID: 156386). For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Dec 20, 2018

- -

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

Nov 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587783017; hg19: chr12-88449443;