12-88084539-TAA-TA

Variant names:

• chr12-88084539-TA-T
• rs11356711
• NM_025114.4:c.4704+46delT

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.4704+46delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (50434 hom., cov: 0)
  • Exomes 𝑓: 0.91 (564349 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.814
• Publications: 6 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 -16 ACMG points.

• BP6: Variant 12-88084539-TA-T is Benign according to our data. Variant chr12-88084539-TA-T is described in ClinVar as Benign. ClinVar VariationId is 261845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.942 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.4704+46delT		intron_variant	Intron 35 of 53	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.4704+46delT		intron_variant	Intron 35 of 53	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes AF: 0.781 AC: 118762 AN: 151998 Hom.: 50432 Cov.: 0

Gnomad AFR AF: 0.411

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: 0.963

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.928

Gnomad OTH AF: 0.821

GnomAD2 exomes AF: 0.894 AC: 197463 AN: 220854 AF XY: 0.901

Gnomad AFR exome AF: 0.395

Gnomad AMR exome AF: 0.922

Gnomad ASJ exome AF: 0.907

Gnomad EAS exome AF: 0.976

Gnomad FIN exome AF: 0.962

Gnomad NFE exome AF: 0.931

Gnomad OTH exome AF: 0.901

GnomAD4 exome AF: 0.913 AC: 1225707 AN: 1342950 Hom.: 564349 Cov.: 0 AF XY: 0.913 AC XY: 613838 AN XY: 672200

African (AFR) AF: 0.394 AC: 11728 AN: 29738

American (AMR) AF: 0.916 AC: 32188 AN: 35124

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 22077 AN: 24444

East Asian (EAS) AF: 0.955 AC: 37201 AN: 38946

South Asian (SAS) AF: 0.892 AC: 68177 AN: 76434

European-Finnish (FIN) AF: 0.961 AC: 49597 AN: 51626

Middle Eastern (MID) AF: 0.890 AC: 3908 AN: 4392

European-Non Finnish (NFE) AF: 0.927 AC: 950812 AN: 1026004

Other (OTH) AF: 0.889 AC: 50019 AN: 56242

GnomAD4 genome AF: 0.781 AC: 118778 AN: 152116 Hom.: 50434 Cov.: 0 AF XY: 0.787 AC XY: 58548 AN XY: 74392

African (AFR) AF: 0.410 AC: 16986 AN: 41454

American (AMR) AF: 0.866 AC: 13227 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 3106 AN: 3472

East Asian (EAS) AF: 0.965 AC: 4999 AN: 5182

South Asian (SAS) AF: 0.898 AC: 4336 AN: 4830

European-Finnish (FIN) AF: 0.963 AC: 10221 AN: 10616

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.928 AC: 63055 AN: 67970

Other (OTH) AF: 0.823 AC: 1738 AN: 2112

Alfa AF: 0.859 Hom.: 10576

Bravo AF: 0.759

Asia WGS AF: 0.882 AC: 3064 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.81
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: rs11356711; hg19: chr12-88478316;