rs386834159

chr12-88071785-CA-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.5850del(p.Phe1950LeufsTer15) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000299 in 1,436,570 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: 0.000030 (0 hom.)
• Consequence: CEP290 NM_025114.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.23

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 12-88071785-CA-C is Pathogenic according to our data. Variant chr12-88071785-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 56740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88071785-CA-C is described in Lovd as [Pathogenic]. Variant chr12-88071785-CA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4	c.5850del	p.Phe1950LeufsTer15	frameshift_variant	42/54	ENST00000552810.6
LOC124902977	XR_007063393.1	n.887-10523del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6	c.5850del	p.Phe1950LeufsTer15	frameshift_variant	42/54	1	NM_025114.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000299 AC: 43 AN: 1436570 Hom.: 0 Cov.: 30 AF XY: 0.0000280 AC XY: 20 AN XY: 713434

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000256

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000372

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Meckel syndrome, type 4 Pathogenic:2

Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 17, 2022	Variant summary: CEP290 c.5850delT (p.Phe1950LeufsX15) 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 in ClinVar (e.g. c.7048C>T [p.Gln2350Ter]; c.6798G>A [p.Trp2266Ter]). The variant allele was found at a frequency of 1.8e-05 in 222022 control chromosomes (gnomAD). c.5850delT has been reported in the literature in multiple individuals affected with Meckel Syndrome (e.g. Baala_2007, Tallila_2009), Leber congenital amaurosis (e.g. Perrault_2007) and Nephronophthisis/Joubert Syndrome (e.g. Tory_2007). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Leber congenital amaurosis Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 25, 2020

- -

Bardet-Biedl syndrome 14 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 13, 2023

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2023

This sequence change creates a premature translational stop signal (p.Phe1950Leufs*15) 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 a spectrum of CEP290-related ciliopathy conditions (PMID: 17345604, 17564974, 21866095, 26667666). ClinVar contains an entry for this variant (Variation ID: 56740). 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

Feb 11, 2022

- -

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: rs386834159; hg19: chr12-88465562;