rs45461003

Variant names:

• chr12-88111649-A-G
• rs45461003
• NM_025114.4:c.2217+45T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_025114.4(CEP290):​c.2217+45T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00741 in 1,467,974 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (51 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.964
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 12-88111649-A-G is Benign according to our data. Variant chr12-88111649-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 261834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	NM_025114.4	MANE Select	c.2217+45T>C		intron	N/A	NP_079390.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	ENST00000552810.6	TSL:1 MANE Select	c.2217+45T>C		intron	N/A	ENSP00000448012.1
	CEP290	ENST00000604024.5	TSL:1	c.1476+45T>C		intron	N/A	ENSP00000473863.1
	CEP290	ENST00000547926.7	TSL:1	n.*130+45T>C		intron	N/A	ENSP00000448573.3

Frequencies

GnomAD3 genomes AF: 0.00634 AC: 965 AN: 152152 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00780

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00878

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00875

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00729 AC: 1209 AN: 165742 AF XY: 0.00780

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.00555

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00874

Gnomad NFE exome AF: 0.00925

Gnomad OTH exome AF: 0.00872

GnomAD4 exome AF: 0.00753 AC: 9908 AN: 1315704 Hom.: 51 Cov.: 21 AF XY: 0.00754 AC XY: 4934 AN XY: 654774

African (AFR) AF: 0.00115 AC: 30 AN: 26194

American (AMR) AF: 0.00625 AC: 145 AN: 23190

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 245 AN: 22538

East Asian (EAS) AF: 0.00 AC: 0 AN: 34474

South Asian (SAS) AF: 0.00394 AC: 263 AN: 66804

European-Finnish (FIN) AF: 0.00933 AC: 479 AN: 51358

Middle Eastern (MID) AF: 0.00858 AC: 46 AN: 5360

European-Non Finnish (NFE) AF: 0.00804 AC: 8297 AN: 1031486

Other (OTH) AF: 0.00742 AC: 403 AN: 54300

GnomAD4 genome AF: 0.00634 AC: 965 AN: 152270 Hom.: 6 Cov.: 32 AF XY: 0.00649 AC XY: 483 AN XY: 74468

African (AFR) AF: 0.00178 AC: 74 AN: 41580

American (AMR) AF: 0.00779 AC: 119 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.00878 AC: 93 AN: 10596

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00875 AC: 595 AN: 68002

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00758 Hom.: 2

Bravo AF: 0.00604

Asia WGS AF: 0.00116 AC: 4 AN: 3468

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 06, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

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	-0.77
CADD	Benign	5.6
DANN	Benign	0.80
PhyloP100		0.96
Mutation Taster		=100/0	polymorphism

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: rs45461003; hg19: chr12-88505426;