rs117852025

Positions:

chr12-88060951-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_025114.4(CEP290):c.6401T>C(p.Ile2134Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00731 in 1,562,170 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0053 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0075 ( 99 hom. )

Consequence

CEP290
NM_025114.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:17

Conservation

PhyloP100: 8.35

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:

CEP290 (HGNC:):

CEP290 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009030223).

BP6

Variant 12-88060951-A-G is Benign according to our data. Variant chr12-88060951-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166829.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, Benign=7}. Variant chr12-88060951-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00528 (803/152154) while in subpopulation SAS AF= 0.0137 (66/4818). AF 95% confidence interval is 0.011. There are 7 homozygotes in gnomad4. There are 382 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP290	NM_025114.4 linkuse as main transcript	c.6401T>C	p.Ile2134Thr	missense_variant	47/54	ENST00000552810.6	NP_079390.3	O15078Q05BJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6 linkuse as main transcript	c.6401T>C	p.Ile2134Thr	missense_variant	47/54	1	NM_025114.4	ENSP00000448012.1		O15078

Frequencies

GnomAD3 genomes

AF:

0.00528

AC:

802

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.0478

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.000851

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00662

Gnomad OTH

AF:

0.00623

GnomAD3 exomes

AF:

0.00758

AC:

1353

AN:

178574

Hom.:

AF XY:

0.00850

AC XY:

804

AN XY:

94596

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00186

Gnomad ASJ exome

AF:

0.0407

Gnomad EAS exome

AF:

0.0000742

Gnomad SAS exome

AF:

0.0145

Gnomad FIN exome

AF:

0.00105

Gnomad NFE exome

AF:

0.00741

Gnomad OTH exome

AF:

0.00670

GnomAD4 exome

AF:

0.00753

AC:

10614

AN:

1410016

Hom.:

Cov.:

AF XY:

0.00782

AC XY:

5446

AN XY:

696548

show subpopulations

Gnomad4 AFR exome

AF:

0.00120

Gnomad4 AMR exome

AF:

0.00241

Gnomad4 ASJ exome

AF:

0.0363

Gnomad4 EAS exome

AF:

0.0000529

Gnomad4 SAS exome

AF:

0.0163

Gnomad4 FIN exome

AF:

0.00111

Gnomad4 NFE exome

AF:

0.00696

Gnomad4 OTH exome

AF:

0.0100

GnomAD4 genome

AF:

0.00528

AC:

803

AN:

152154

Hom.:

Cov.:

AF XY:

0.00514

AC XY:

382

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00152

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.0478

Gnomad4 EAS

AF:

0.000774

Gnomad4 SAS

AF:

0.0137

Gnomad4 FIN

AF:

0.000851

Gnomad4 NFE

AF:

0.00665

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00769

Hom.:

Bravo

AF:

0.00506

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000838

AC:

ESP6500EA

AF:

0.00754

AC:

ExAC

AF:

0.00543

AC:

639

Asia WGS

AF:

0.00347

AC:

AN:

3468

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:17

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CEP290: BS1, BS2 -

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 07, 2016	- -

Joubert syndrome 5

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Meckel syndrome, type 4

Uncertain:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine 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.

Jan 06, 2020

- -

Bardet-Biedl syndrome 14

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. -

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

Jan 31, 2024

- -

Intellectual disability

Benign:1

Benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

.;.;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

T;T;T

MetaRNN

Benign

0.0090

T;T;T

MetaSVM

Uncertain

-0.065

MutationAssessor

Benign

2.0

.;.;M

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.9

N;N;N

REVEL

Uncertain

0.41

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.019

D;T;D

Polyphen

1.0

.;.;D

Vest4

0.83

MVP

0.88

MPC

0.38

ClinPred

0.017

GERP RS

6.0

Varity_R

0.17

gMVP

0.35

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

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