12-88111301-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_025114.4(CEP290):c.2268A>G(p.Ser756Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.9 in 1,558,632 control chromosomes in the GnomAD database, including 641,375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S756S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.78 ( 50357 hom., cov: 30)

Exomes 𝑓: 0.91 ( 591018 hom. )

Consequence

CEP290
NM_025114.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.347

Publications

24 publications found

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 Gene-Disease associations (from GenCC):

CEP290-related ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Joubert syndrome 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Bardet-Biedl syndrome 14
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis 10
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome with oculorenal defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Senior-Loken syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CEP290 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 12-88111301-T-C is Benign according to our data. Variant chr12-88111301-T-C is described in ClinVar as Benign. ClinVar VariationId is 126249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.347 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4 link	c.2268A>G	p.Ser756Ser	synonymous_variant	Exon 22 of 54	ENST00000552810.6	NP_079390.3	O15078Q05BJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6 link	c.2268A>G	p.Ser756Ser	synonymous_variant	Exon 22 of 54	1	NM_025114.4	ENSP00000448012.1		O15078

Frequencies

GnomAD3 genomes

AF:

0.781

AC:

118579

AN:

151766

Hom.:

50355

Cov.:

show subpopulations

Gnomad AFR

AF:

0.410

Gnomad AMI

AF:

0.923

Gnomad AMR

AF:

0.866

Gnomad ASJ

AF:

0.895

Gnomad EAS

AF:

0.965

Gnomad SAS

AF:

0.897

Gnomad FIN

AF:

0.962

Gnomad MID

AF:

0.921

Gnomad NFE

AF:

0.928

Gnomad OTH

AF:

0.821

GnomAD2 exomes

AF:

0.894

AC:

165101

AN:

184714

AF XY:

0.900

show subpopulations

Gnomad AFR exome

AF:

0.386

Gnomad AMR exome

AF:

0.921

Gnomad ASJ exome

AF:

0.907

Gnomad EAS exome

AF:

0.975

Gnomad FIN exome

AF:

0.961

Gnomad NFE exome

AF:

0.927

Gnomad OTH exome

AF:

0.898

GnomAD4 exome

AF:

0.913

AC:

1283933

AN:

1406750

Hom.:

591018

Cov.:

AF XY:

0.913

AC XY:

635726

AN XY:

696134

show subpopulations

African (AFR)

AF:

0.393

AC:

12472

AN:

31748

American (AMR)

AF:

0.915

AC:

33013

AN:

36062

Ashkenazi Jewish (ASJ)

AF:

0.903

AC:

22692

AN:

25122

East Asian (EAS)

AF:

0.954

AC:

35439

AN:

37152

South Asian (SAS)

AF:

0.891

AC:

69567

AN:

78050

European-Finnish (FIN)

AF:

0.960

AC:

49152

AN:

51178

Middle Eastern (MID)

AF:

0.897

AC:

5044

AN:

5624

European-Non Finnish (NFE)

AF:

0.927

AC:

1004932

AN:

1083742

Other (OTH)

AF:

0.889

AC:

51622

AN:

58072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

4419

8839

13258

17678

22097

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21176

42352

63528

84704

105880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.781

AC:

118595

AN:

151882

Hom.:

50357

Cov.:

AF XY:

0.787

AC XY:

58410

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.409

AC:

16920

AN:

41340

American (AMR)

AF:

0.866

AC:

13212

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.895

AC:

3106

AN:

3472

East Asian (EAS)

AF:

0.965

AC:

4958

AN:

5138

South Asian (SAS)

AF:

0.898

AC:

4326

AN:

4818

European-Finnish (FIN)

AF:

0.962

AC:

10190

AN:

10590

Middle Eastern (MID)

AF:

0.918

AC:

270

AN:

294

European-Non Finnish (NFE)

AF:

0.928

AC:

63038

AN:

67956

Other (OTH)

AF:

0.823

AC:

1733

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

889

1778

2668

3557

4446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

832

1664

2496

3328

4160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.878

Hom.:

187487

Bravo

AF:

0.759

Asia WGS

AF:

0.882

AC:

3065

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Senior-Loken syndrome 6

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leber congenital amaurosis

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Bardet-Biedl syndrome 14

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meckel syndrome, type 4

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Joubert syndrome 5

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

0.35

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over