12-88089495-TAA-TA

Variant names:

• chr12-88089495-TA-T
• rs10717563
• NM_025114.4:c.3574-9delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_025114.4(CEP290):​c.3574-9delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59932 hom., cov: 0)
  • Exomes 𝑓: 0.94 (552196 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.208
• Publications: 5 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: 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-88089495-TA-T is Benign according to our data. Variant chr12-88089495-TA-T is described in ClinVar as Benign. ClinVar VariationId is 96170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

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.3574-9delT		intron	N/A	NP_079390.3	O15078

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	ENST00000552810.6	TSL:1 MANE Select	c.3574-9delT		intron	N/A	ENSP00000448012.1	O15078
	CEP290	ENST00000547691.8	TSL:1	c.856-9delT		intron	N/A	ENSP00000446905.3	A0A5K1VW81
	CEP290	ENST00000675476.1		c.4435-9delT		intron	N/A	ENSP00000502161.1	A0A6Q8PGB1

Frequencies

GnomAD3 genomes AF: 0.882 AC: 133923 AN: 151880 Hom.: 59916 Cov.: 0

Gnomad AFR AF: 0.713

Gnomad AMI AF: 0.953

Gnomad AMR AF: 0.919

Gnomad ASJ AF: 0.896

Gnomad EAS AF: 0.988

Gnomad SAS AF: 0.901

Gnomad FIN AF: 0.988

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.948

Gnomad OTH AF: 0.893

GnomAD2 exomes AF: 0.931 AC: 76331 AN: 82002 AF XY: 0.932

Gnomad AFR exome AF: 0.705

Gnomad AMR exome AF: 0.939

Gnomad ASJ exome AF: 0.913

Gnomad EAS exome AF: 0.990

Gnomad FIN exome AF: 0.987

Gnomad NFE exome AF: 0.950

Gnomad OTH exome AF: 0.929

GnomAD4 exome AF: 0.942 AC: 1170044 AN: 1242604 Hom.: 552196 Cov.: 0 AF XY: 0.941 AC XY: 565434 AN XY: 600924

African (AFR) AF: 0.708 AC: 19145 AN: 27040

American (AMR) AF: 0.939 AC: 16693 AN: 17786

Ashkenazi Jewish (ASJ) AF: 0.906 AC: 17434 AN: 19244

East Asian (EAS) AF: 0.993 AC: 33225 AN: 33462

South Asian (SAS) AF: 0.898 AC: 45809 AN: 51004

European-Finnish (FIN) AF: 0.984 AC: 36974 AN: 37580

Middle Eastern (MID) AF: 0.916 AC: 4692 AN: 5120

European-Non Finnish (NFE) AF: 0.949 AC: 948713 AN: 1000178

Other (OTH) AF: 0.925 AC: 47359 AN: 51190

GnomAD4 genome AF: 0.881 AC: 133981 AN: 151998 Hom.: 59932 Cov.: 0 AF XY: 0.885 AC XY: 65778 AN XY: 74286

African (AFR) AF: 0.712 AC: 29493 AN: 41394

American (AMR) AF: 0.919 AC: 14034 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.896 AC: 3111 AN: 3472

East Asian (EAS) AF: 0.988 AC: 5083 AN: 5144

South Asian (SAS) AF: 0.902 AC: 4350 AN: 4824

European-Finnish (FIN) AF: 0.988 AC: 10437 AN: 10568

Middle Eastern (MID) AF: 0.929 AC: 273 AN: 294

European-Non Finnish (NFE) AF: 0.947 AC: 64446 AN: 68018

Other (OTH) AF: 0.894 AC: 1887 AN: 2110

Alfa AF: 0.914 Hom.: 3709

Bravo AF: 0.869

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Leber congenital amaurosis (2)
-	-	1	Bardet-Biedl syndrome (1)
-	-	1	Bardet-Biedl syndrome 14 (1)
-	-	1	Joubert syndrome (1)
-	-	1	Joubert syndrome 5 (1)
-	-	1	Meckel syndrome, type 4 (1)
-	-	1	Meckel-Gruber syndrome (1)
-	-	1	Meckel-Gruber syndrome;C0687120:Nephronophthisis;C5979921:Joubert syndrome (1)
-	-	1	not provided (1)
-	-	1	Renal dysplasia and retinal aplasia (1)
-	-	1	Senior-Loken syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10717563; hg19: chr12-88483272;