chr12-88107101-A-AAAAAC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_025114.4(CEP290):c.2484-8_2484-4dupGTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,497,774 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 8 hom. )

Consequence

CEP290
NM_025114.4 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:10

Conservation

PhyloP100: 0.0460

Publications

1 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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 12-88107101-A-AAAAAC is Benign according to our data. Variant chr12-88107101-A-AAAAAC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220050.

BS2

High Homozygotes in GnomAdExome4 at 8 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.2484-8_2484-4dupGTTTT		splice_region intron	N/A	NP_079390.3	O15078

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CEP290	ENST00000552810.6	TSL:1 MANE Select	c.2484-4_2484-3insGTTTT	splice_region intron	N/A	ENSP00000448012.1	O15078
CEP290	ENST00000604024.5	TSL:1	c.1743-4_1743-3insGTTTT	splice_region intron	N/A	ENSP00000473863.1	S4R322
CEP290	ENST00000675476.1		c.3345-4_3345-3insGTTTT	splice_region intron	N/A	ENSP00000502161.1	A0A6Q8PGB1

Frequencies

GnomAD3 genomes

AF:

0.000868

AC:

132

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000742

AC:

103

AN:

138756

AF XY:

0.000626

show subpopulations

Gnomad AFR exome

AF:

0.000117

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.000132

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000322

Gnomad NFE exome

AF:

0.00152

Gnomad OTH exome

AF:

0.000515

GnomAD4 exome

AF:

0.00108

AC:

1451

AN:

1345586

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

736

AN XY:

665784

show subpopulations

African (AFR)

AF:

0.000136

AC:

AN:

29504

American (AMR)

AF:

0.000284

AC:

AN:

28192

Ashkenazi Jewish (ASJ)

AF:

0.000124

AC:

AN:

24178

East Asian (EAS)

AF:

0.00

AC:

AN:

35802

South Asian (SAS)

AF:

0.0000412

AC:

AN:

72852

European-Finnish (FIN)

AF:

0.000317

AC:

AN:

47302

Middle Eastern (MID)

AF:

0.000649

AC:

AN:

4620

European-Non Finnish (NFE)

AF:

0.00131

AC:

1367

AN:

1047172

Other (OTH)

AF:

0.000858

AC:

AN:

55964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

149

224

298

373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.000867

AC:

132

AN:

152188

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41542

American (AMR)

AF:

0.000720

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00160

AC:

109

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000546

Hom.:

Bravo

AF:

0.000850

Asia WGS

AF:

0.000290

AC:

AN:

3460

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

Leber congenital amaurosis (2)

not specified (2)

Bardet-Biedl syndrome (1)

Intellectual disability (1)

Joubert syndrome (1)

Meckel-Gruber syndrome (1)

Meckel-Gruber syndrome;C0687120:Nephronophthisis;C5979921:Joubert syndrome (1)

Renal dysplasia and retinal aplasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.046

Mutation Taster

=96/4

polymorphism

(source)

Splicing

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