rs367600498

chr12-88115193-CAG-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_025114.4(CEP290):c.1825-13_1825-12del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,328,984 control chromosomes in the GnomAD database, including 89 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (7 hom., cov: 32)
  • Exomes 𝑓: 0.011 (82 hom.)
• Consequence: CEP290 NM_025114.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.448

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 -16 ACMG points.

• BP6: Variant 12-88115193-CAG-C is Benign according to our data. Variant chr12-88115193-CAG-C is described in ClinVar as [Likely_benign]. Clinvar id is 235609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88115193-CAG-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00721 (1096/151956) while in subpopulation NFE AF= 0.0115 (784/67916). AF 95% confidence interval is 0.0109. There are 7 homozygotes in gnomad4. There are 487 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4	c.1825-13_1825-12del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000552810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6	c.1825-13_1825-12del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_025114.4	P4

Frequencies

GnomAD3 genomes AF: 0.00722 AC: 1097 AN: 151840 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00846

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00493

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00691 AC: 1043 AN: 150848 Hom.: 7 AF XY: 0.00682 AC XY: 549 AN XY: 80444

Gnomad AFR exome AF: 0.00177

Gnomad AMR exome AF: 0.00476

Gnomad ASJ exome AF: 0.00753

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000771

Gnomad FIN exome AF: 0.00880

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00607

GnomAD4 exome AF: 0.0108 AC: 12654 AN: 1177028 Hom.: 82 AF XY: 0.0104 AC XY: 6128 AN XY: 591278

Gnomad4 AFR exome AF: 0.00141

Gnomad4 AMR exome AF: 0.00560

Gnomad4 ASJ exome AF: 0.00824

Gnomad4 EAS exome AF: 0.0000274

Gnomad4 SAS exome AF: 0.000623

Gnomad4 FIN exome AF: 0.00931

Gnomad4 NFE exome AF: 0.0126

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.00721 AC: 1096 AN: 151956 Hom.: 7 Cov.: 32 AF XY: 0.00656 AC XY: 487 AN XY: 74282

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.00845

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00493

Gnomad4 NFE AF: 0.0115

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00931 Hom.: 2

Bravo AF: 0.00756

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs367600498; hg19: chr12-88508970;