12-88103061-C-G

Variant names:

• chr12-88103061-C-G
• rs2471532
• NM_025114.4:c.2818-50G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025114.4(CEP290):​c.2818-50G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.9 in 1,280,644 control chromosomes in the GnomAD database, including 526,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (50396 hom., cov: 31)
  • Exomes 𝑓: 0.92 (476443 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.639
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-88103061-C-G is Benign according to our data. Variant chr12-88103061-C-G is described in ClinVar as Benign. ClinVar VariationId is 126253.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.2818-50G>C		intron_variant	Intron 25 of 53	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.2818-50G>C		intron_variant	Intron 25 of 53	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes AF: 0.781 AC: 118678 AN: 151884 Hom.: 50394 Cov.: 31

Gnomad AFR AF: 0.410

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.866

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.965

Gnomad SAS AF: 0.898

Gnomad FIN AF: 0.963

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.928

Gnomad OTH AF: 0.821

GnomAD2 exomes AF: 0.904 AC: 68734 AN: 76008 AF XY: 0.910

Gnomad AFR exome AF: 0.399

Gnomad AMR exome AF: 0.904

Gnomad ASJ exome AF: 0.908

Gnomad EAS exome AF: 0.969

Gnomad FIN exome AF: 0.963

Gnomad NFE exome AF: 0.927

Gnomad OTH exome AF: 0.904

GnomAD4 exome AF: 0.916 AC: 1033778 AN: 1128642 Hom.: 476443 Cov.: 14 AF XY: 0.916 AC XY: 509847 AN XY: 556586

African (AFR) AF: 0.410 AC: 8752 AN: 21326

American (AMR) AF: 0.900 AC: 10159 AN: 11288

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 18006 AN: 19946

East Asian (EAS) AF: 0.948 AC: 26691 AN: 28164

South Asian (SAS) AF: 0.892 AC: 43967 AN: 49282

European-Finnish (FIN) AF: 0.961 AC: 44198 AN: 45988

Middle Eastern (MID) AF: 0.886 AC: 3248 AN: 3664

European-Non Finnish (NFE) AF: 0.928 AC: 836490 AN: 901524

Other (OTH) AF: 0.891 AC: 42267 AN: 47460

GnomAD4 genome AF: 0.781 AC: 118694 AN: 152002 Hom.: 50396 Cov.: 31 AF XY: 0.787 AC XY: 58488 AN XY: 74326

African (AFR) AF: 0.410 AC: 16968 AN: 41418

American (AMR) AF: 0.866 AC: 13225 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 3104 AN: 3470

East Asian (EAS) AF: 0.965 AC: 4990 AN: 5172

South Asian (SAS) AF: 0.899 AC: 4327 AN: 4814

European-Finnish (FIN) AF: 0.963 AC: 10195 AN: 10590

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

European-Non Finnish (NFE) AF: 0.928 AC: 63036 AN: 67948

Other (OTH) AF: 0.822 AC: 1737 AN: 2112

Alfa AF: 0.856 Hom.: 9636

Bravo AF: 0.759

Asia WGS AF: 0.880 AC: 3055 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Senior-Loken syndrome 6 Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome 14 Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meckel syndrome, type 4 Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 5 Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.2
DANN	Benign	0.59
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2471532; hg19: chr12-88496838;