NM_025114.4:c.829G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.02

Publications

18 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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 -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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025114.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	NM_025114.4	MANE Select	c.829G>C	p.Glu277Gln	missense	Exon 10 of 54	NP_079390.3	O15078

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CEP290	ENST00000552810.6	TSL:1 MANE Select	c.829G>C	p.Glu277Gln	missense	Exon 10 of 54	ENSP00000448012.1	O15078
CEP290	ENST00000547926.7	TSL:1	n.829G>C		non_coding_transcript_exon	Exon 10 of 21	ENSP00000448573.3	F8VS29
CEP290	ENST00000675476.1		c.829G>C	p.Glu277Gln	missense	Exon 10 of 56	ENSP00000502161.1	A0A6Q8PGB1

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

GnomAD2 exomes

AF:

0.0136

AC:

1528

AN:

112520

AF XY:

0.0126

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 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

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:

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:

AN:

5364

European-Non Finnish (NFE)

AF:

0.0189

AC:

19119

AN:

1010682

Other (OTH)

AF:

0.0153

AC:

824

AN:

53884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

868

1735

2603

3470

4338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

742

1484

2226

2968

3710

<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:

0.0161

AC:

2450

AN:

151870

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1214

AN XY:

74214

show subpopulations

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:

AN:

3468

East Asian (EAS)

AF:

0.0236

AC:

122

AN:

5178

South Asian (SAS)

AF:

0.00291

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0259

AC:

274

AN:

10578

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0190

AC:

1289

AN:

67770

Other (OTH)

AF:

0.0238

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

116

231

347

462

578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0152

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (5)

Bardet-Biedl syndrome 14 (1)

Joubert syndrome 5 (1)

Leber congenital amaurosis (1)

Leber congenital amaurosis 10 (1)

Meckel syndrome, type 4 (1)

Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis (1)

Retinal dystrophy (1)

Senior-Loken syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.5

PhyloP100

7.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.5

REVEL

Benign

0.22

Sift

Benign

0.11

Sift4G

Uncertain

0.024

Polyphen

1.0

Vest4

0.39

MPC

0.24

ClinPred

0.0071

GERP RS

4.7

PromoterAI

0.0034

Neutral

(source)

Varity_R

0.25

gMVP

0.47

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over