12-88111301-T-C

Position:

• chr12-88111301-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_025114.4(CEP290):​c.2268A>G​(p.Ser756=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.9 in 1,558,632 control chromosomes in the GnomAD database, including 641,375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S756S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.78 (50357 hom., cov: 30)
  • Exomes 𝑓: 0.91 (591018 hom.)
• Consequence: CEP290 NM_025114.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.347

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 12-88111301-T-C is Benign according to our data. Variant chr12-88111301-T-C is described in ClinVar as [Benign]. Clinvar id is 126249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88111301-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.347 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4	c.2268A>G	p.Ser756=	synonymous_variant	22/54	ENST00000552810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6	c.2268A>G	p.Ser756=	synonymous_variant	22/54	1	NM_025114.4	P4

Frequencies

GnomAD3 genomes AF: 0.781 AC: 118579 AN: 151766 Hom.: 50355 Cov.: 30

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: 0.897

Gnomad FIN AF: 0.962

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.928

Gnomad OTH AF: 0.821

GnomAD3 exomes AF: 0.894 AC: 165101 AN: 184714 Hom.: 75435 AF XY: 0.900 AC XY: 89548 AN XY: 99474

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.921

Gnomad ASJ exome AF: 0.907

Gnomad EAS exome AF: 0.975

Gnomad SAS exome AF: 0.888

Gnomad FIN exome AF: 0.961

Gnomad NFE exome AF: 0.927

Gnomad OTH exome AF: 0.898

GnomAD4 exome AF: 0.913 AC: 1283933 AN: 1406750 Hom.: 591018 Cov.: 31 AF XY: 0.913 AC XY: 635726 AN XY: 696134

Gnomad4 AFR exome AF: 0.393

Gnomad4 AMR exome AF: 0.915

Gnomad4 ASJ exome AF: 0.903

Gnomad4 EAS exome AF: 0.954

Gnomad4 SAS exome AF: 0.891

Gnomad4 FIN exome AF: 0.960

Gnomad4 NFE exome AF: 0.927

Gnomad4 OTH exome AF: 0.889

GnomAD4 genome AF: 0.781 AC: 118595 AN: 151882 Hom.: 50357 Cov.: 30 AF XY: 0.787 AC XY: 58410 AN XY: 74222

Gnomad4 AFR AF: 0.409

Gnomad4 AMR AF: 0.866

Gnomad4 ASJ AF: 0.895

Gnomad4 EAS AF: 0.965

Gnomad4 SAS AF: 0.898

Gnomad4 FIN AF: 0.962

Gnomad4 NFE AF: 0.928

Gnomad4 OTH AF: 0.823

Alfa AF: 0.891 Hom.: 86739

Bravo AF: 0.759

Asia WGS AF: 0.882 AC: 3065 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -

Senior-Loken syndrome 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Leber congenital amaurosis Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Bardet-Biedl syndrome 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Meckel syndrome, type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Joubert syndrome 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2468255; hg19: chr12-88505078;