12-88129717-C-G

Position:

chr12-88129717-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000552810.6(CEP290):c.829G>C(p.Glu277Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0177 in 1,448,302 control chromosomes in the GnomAD database, including 309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 27 hom., cov: 32)

Exomes 𝑓: 0.018 ( 282 hom. )

Consequence

CEP290
ENST00000552810.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 7.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00445202).

BP6

Variant 12-88129717-C-G is Benign according to our data. Variant chr12-88129717-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 126269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88129717-C-G is described in Lovd as [Likely_benign]. Variant chr12-88129717-C-G is described in Lovd as [Benign]. Variant chr12-88129717-C-G is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0161 (2450/151870) while in subpopulation EAS AF= 0.0236 (122/5178). AF 95% confidence interval is 0.0203. There are 27 homozygotes in gnomad4. There are 1214 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP290	NM_025114.4 linkuse as main transcript	c.829G>C	p.Glu277Gln	missense_variant	10/54	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6 linkuse as main transcript	c.829G>C	p.Glu277Gln	missense_variant	10/54	1	NM_025114.4	ENSP00000448012	P4

Frequencies

GnomAD3 genomes

AF:

0.0161

AC:

2445

AN:

151752

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00785

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0223

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.0235

Gnomad SAS

AF:

0.00291

Gnomad FIN

AF:

0.0259

Gnomad MID

AF:

0.00645

Gnomad NFE

AF:

0.0190

Gnomad OTH

AF:

0.0240

GnomAD3 exomes

AF:

0.0136

AC:

1528

AN:

112520

Hom.:

AF XY:

0.0126

AC XY:

760

AN XY:

60462

show subpopulations

Gnomad AFR exome

AF:

0.00607

Gnomad AMR exome

AF:

0.0104

Gnomad ASJ exome

AF:

0.00141

Gnomad EAS exome

AF:

0.0107

Gnomad SAS exome

AF:

0.00281

Gnomad FIN exome

AF:

0.0248

Gnomad NFE exome

AF:

0.0176

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.0179

AC:

23178

AN:

1296432

Hom.:

282

Cov.:

AF XY:

0.0176

AC XY:

11310

AN XY:

642210

show subpopulations

Gnomad4 AFR exome

AF:

0.00613

Gnomad4 AMR exome

AF:

0.0129

Gnomad4 ASJ exome

AF:

0.00132

Gnomad4 EAS exome

AF:

0.0413

Gnomad4 SAS exome

AF:

0.00335

Gnomad4 FIN exome

AF:

0.0235

Gnomad4 NFE exome

AF:

0.0189

Gnomad4 OTH exome

AF:

0.0153

GnomAD4 genome

AF:

0.0161

AC:

2450

AN:

151870

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1214

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.00795

Gnomad4 AMR

AF:

0.0223

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.0236

Gnomad4 SAS

AF:

0.00291

Gnomad4 FIN

AF:

0.0259

Gnomad4 NFE

AF:

0.0190

Gnomad4 OTH

AF:

0.0238

Alfa

AF:

0.0152

Hom.:

Bravo

AF:

0.0146

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0226

AC:

ESP6500AA

AF:

0.00751

AC:

ESP6500EA

AF:

0.0171

AC:

132

ExAC

AF:

0.00627

AC:

562

Asia WGS

AF:

0.0100

AC:

AN:

3446

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27894351, 27884173, 21153841) -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CEP290: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2014	- -

Senior-Loken syndrome 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Leber congenital amaurosis 10

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Leber congenital amaurosis

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Bardet-Biedl syndrome 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Meckel syndrome, type 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Joubert syndrome 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

.;T;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.5

.;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.5

N;N;.

REVEL

Benign

0.22

Sift

Benign

0.11

T;T;.

Sift4G

Uncertain

0.024

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.39

MPC

0.24

ClinPred

0.0071

GERP RS

4.7

Varity_R

0.25

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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