rs1227765663

Variant names:

• chr12-88096967-C-T
• rs1227765663
• NM_025114.4:c.3024G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_025114.4(CEP290):​c.3024G>A​(p.Glu1008Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000247 in 1,416,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: CEP290 NM_025114.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.377
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 12-88096967-C-T is Benign according to our data. Variant chr12-88096967-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 530924.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.377 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	NM_025114.4	MANE Select	c.3024G>A	p.Glu1008Glu	synonymous	Exon 27 of 54	NP_079390.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	ENST00000552810.6	TSL:1 MANE Select	c.3024G>A	p.Glu1008Glu	synonymous	Exon 27 of 54	ENSP00000448012.1
	CEP290	ENST00000547691.8	TSL:1	c.306G>A	p.Glu102Glu	synonymous	Exon 3 of 28	ENSP00000446905.3
	CEP290	ENST00000604024.5	TSL:1	c.2283G>A	p.Glu761Glu	synonymous	Exon 19 of 20	ENSP00000473863.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000105 AC: 2 AN: 190374 AF XY: 0.00000985

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000251

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000247 AC: 35 AN: 1416938 Hom.: 0 Cov.: 27 AF XY: 0.0000228 AC XY: 16 AN XY: 701058

African (AFR) AF: 0.00 AC: 0 AN: 32596

American (AMR) AF: 0.00 AC: 0 AN: 39034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25536

East Asian (EAS) AF: 0.00 AC: 0 AN: 38258

South Asian (SAS) AF: 0.00 AC: 0 AN: 80026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.0000313 AC: 34 AN: 1086340

Other (OTH) AF: 0.0000171 AC: 1 AN: 58646

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis Benign:1

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.52
DANN	Benign	0.39
PhyloP100		-0.38

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: rs1227765663; hg19: chr12-88490744;