12-88129717-C-G

Variant names:

• chr12-88129717-C-G
• rs45502896
• NM_025114.4:c.829G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025114.4(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 NM_025114.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 7.02
• Publications: 18 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 126269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.829G>C	p.Glu277Gln	missense_variant	Exon 10 of 54	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.829G>C	p.Glu277Gln	missense_variant	Exon 10 of 54	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2445 AN: 151752 Hom.: 27 Cov.: 32

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

GnomAD2 exomes AF: 0.0136 AC: 1528 AN: 112520 AF XY: 0.0126

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 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.: 24 AF XY: 0.0176 AC XY: 11310 AN XY: 642210

African (AFR) AF: 0.00613 AC: 163 AN: 26586

American (AMR) AF: 0.0129 AC: 332 AN: 25648

Ashkenazi Jewish (ASJ) AF: 0.00132 AC: 31 AN: 23450

East Asian (EAS) AF: 0.0413 AC: 1310 AN: 31750

South Asian (SAS) AF: 0.00335 AC: 237 AN: 70656

European-Finnish (FIN) AF: 0.0235 AC: 1139 AN: 48412

Middle Eastern (MID) AF: 0.00429 AC: 23 AN: 5364

European-Non Finnish (NFE) AF: 0.0189 AC: 19119 AN: 1010682

Other (OTH) AF: 0.0153 AC: 824 AN: 53884

GnomAD4 genome AF: 0.0161 AC: 2450 AN: 151870 Hom.: 27 Cov.: 32 AF XY: 0.0164 AC XY: 1214 AN XY: 74214

African (AFR) AF: 0.00795 AC: 330 AN: 41534

American (AMR) AF: 0.0223 AC: 339 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.0236 AC: 122 AN: 5178

South Asian (SAS) AF: 0.00291 AC: 14 AN: 4814

European-Finnish (FIN) AF: 0.0259 AC: 274 AN: 10578

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.0190 AC: 1289 AN: 67770

Other (OTH) AF: 0.0238 AC: 50 AN: 2104

Alfa AF: 0.0152 Hom.: 8

Bravo AF: 0.0146

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0226 AC: 87

ESP6500AA AF: 0.00751 AC: 26

ESP6500EA AF: 0.0171 AC: 132

ExAC AF: 0.00627 AC: 562

Asia WGS AF: 0.0100 AC: 36 AN: 3446

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Department of Ophthalmology and Visual Sciences Kyoto University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CEP290: BS1, BS2 -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27894351, 27884173, 21153841) -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:5

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Senior-Loken syndrome 6 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: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

- -

Leber congenital amaurosis 10 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Bardet-Biedl syndrome 14 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 syndrome, type 4 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Joubert syndrome 5 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	.;T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.5	.;M;.
PhyloP100		7.0
PrimateAI	Uncertain	0.54	T
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	T
GERP RS		4.7
PromoterAI		0.0034	Neutral
Varity_R		0.25
gMVP		0.47
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs45502896; hg19: chr12-88523494;