rs62640570

chr12-88093903-AT-Achr12-88093903-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.3175del(p.Ile1059Ter) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000891 in 1,458,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CEP290 NM_025114.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.89

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 12-88093903-AT-A is Pathogenic according to our data. Variant chr12-88093903-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 56735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88093903-AT-A is described in Lovd as [Pathogenic]. Variant chr12-88093903-AT-A is described in Lovd as [Likely_pathogenic]. Variant chr12-88093903-AT-A is described in Lovd as [Pathogenic]. Variant chr12-88093903-AT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4	c.3175del	p.Ile1059Ter	frameshift_variant	28/54	ENST00000552810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6	c.3175del	p.Ile1059Ter	frameshift_variant	28/54	1	NM_025114.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1458758 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 725652

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome 14 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 13, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 20, 2021

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with Meckel syndrome (PMID: 17564974). ClinVar contains an entry for this variant (Variation ID: 56735). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Ile1059*) 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). -

Meckel syndrome, type 4 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

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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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 28, 2022

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs62640570; hg19: chr12-88487680;