rs587783017

chr12-88055666-AT-Achr12-88055666-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.6869del(p.Asn2290IlefsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,401,284 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CEP290 NM_025114.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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-AT-A is Pathogenic according to our data. Variant chr12-88055666-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 654872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88055666-AT-A is described in Lovd as [Pathogenic]. Variant chr12-88055666-AT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4	c.6869del	p.Asn2290IlefsTer11	frameshift_variant	50/54	ENST00000552810.6
LOC124902977	XR_007063393.1	n.772+402del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6	c.6869del	p.Asn2290IlefsTer11	frameshift_variant	50/54	1	NM_025114.4	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 151800 Hom.: 0 Cov.: 32 FAILED QC

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 46 AN: 1401284 Hom.: 0 Cov.: 29 AF XY: 0.0000274 AC XY: 19 AN XY: 692698

Gnomad4 AFR exome AF: 0.000158

Gnomad4 AMR exome AF: 0.000176

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000105

Gnomad4 SAS exome AF: 0.0000789

Gnomad4 FIN exome AF: 0.0000393

Gnomad4 NFE exome AF: 0.0000176

Gnomad4 OTH exome AF: 0.0000687

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000659 AC: 1 AN: 151800 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74134

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CEP290-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This frameshifting variant in exon 50 of 54 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in CEP290 is an established mechanism of disease (PMID: 32600475, 20301500, 16909394, 20690115). This variant has been previously reported as a compound heterozygous change in patients with early-onset chronic kidney disease and cerebello-oculo-renal syndrome (also known as Joubert syndrome) (PMID: 29801666, 33532864, 20690115). The c.6869del (p.Asn2290IlefsTer11) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.02% (35/161872), and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, c.6869del (p.Asn2290IlefsTer11) is classified as Pathogenic. -

Bardet-Biedl syndrome 14 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 18, 2023

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change creates a premature translational stop signal (p.Asn2290Ilefs*11) 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 Joubert syndrome or nephronopthisis (PMID: 17409309). This variant is also known as NPHP6. ClinVar contains an entry for this variant (Variation ID: 654872). For these reasons, this variant has been classified as Pathogenic. -

Joubert syndrome 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Molecular Biology Laboratory, Fundació Puigvert

Feb 01, 2020

- -

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;