chr12-88058868-C-T

Position:

chr12-88058868-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000552810.6(CEP290):c.6798G>A(p.Trp2266Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

CEP290
ENST00000552810.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.64

Variant links:

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]

CEP290 links:

LOC124902977 (HGNC:):

LOC124902977 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 12-88058868-C-T is Pathogenic according to our data. Variant chr12-88058868-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 497937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88058868-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP290	NM_025114.4 linkuse as main transcript	c.6798G>A	p.Trp2266Ter	stop_gained	49/54	ENST00000552810.6	NP_079390.3
LOC124902977	XR_007063393.1 linkuse as main transcript	n.886+1848C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6 linkuse as main transcript	c.6798G>A	p.Trp2266Ter	stop_gained	49/54	1	NM_025114.4	ENSP00000448012	P4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000133

AC:

AN:

248970

Hom.:

AF XY:

0.000170

AC XY:

AN XY:

135072

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00167

Gnomad SAS exome

AF:

0.0000982

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461472

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726996

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000504

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Kidney disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 24, 2021

- -

CEP290-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 20, 2022

Variant summary: CEP290 c.6798G>A (p.Trp2266X) 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 0.00013 in 251868 control chromosomes (gnomAD and Kausthubham_2021). It is seen predominantly within the East Asian subpopulation in the gnomAD database at a frequency of 0.0017, and has been reported at a frequency of 0.0025 in Han Chinese population (Wei_2021). However, this frequency allows no specific conclusions to be made about variant significance. c.6798G>A has been reported in the literature in at least one individual affected with Leber congenital amaurosis (e.g. Zhu_2021) and in compound heterozygous individuals with clinical symptoms such as episodic ataxia and retinal dystrophy (e.g.Hamed_2020, Hull_2020), which are features of some CEP290-Related Disorders. These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Leber congenital amaurosis 10

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000497937). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 18, 2016

- -

Bardet-Biedl syndrome 14

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 28, 2024

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change creates a premature translational stop signal (p.Trp2266*) 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 (rs760540562, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. ClinVar contains an entry for this variant (Variation ID: 497937). 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

Jan 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.92

MutationTaster

Benign

1.0

A;A;A;A

Vest4

0.94

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over