rs17015438

Positions:

• chr12-88077197-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000552810.6(CEP290):​c.5709+25A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,593,292 control chromosomes in the GnomAD database, including 668 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (175 hom., cov: 32)
  • Exomes 𝑓: 0.021 (493 hom.)
• Consequence: CEP290 ENST00000552810.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.62

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]

LOC124902977 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-88077197-T-G is Benign according to our data. Variant chr12-88077197-T-G is described in ClinVar as [Benign]. Clinvar id is 126264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88077197-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP290	NM_025114.4	c.5709+25A>C		intron_variant		ENST00000552810.6	NP_079390.3
LOC124902977	XR_007063393.1	n.887-5116T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.5709+25A>C		intron_variant		1	NM_025114.4	ENSP00000448012	P4

Frequencies

GnomAD3 genomes AF: 0.0376 AC: 5720 AN: 151982 Hom.: 172 Cov.: 32

Gnomad AFR AF: 0.0836

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0289

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0235

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0191

Gnomad OTH AF: 0.0360

GnomAD3 exomes AF: 0.0200 AC: 4680 AN: 233686 Hom.: 86 AF XY: 0.0186 AC XY: 2355 AN XY: 126820

Gnomad AFR exome AF: 0.0825

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.00134

Gnomad EAS exome AF: 0.0139

Gnomad SAS exome AF: 0.00314

Gnomad FIN exome AF: 0.0236

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0189

GnomAD4 exome AF: 0.0213 AC: 30728 AN: 1441192 Hom.: 493 Cov.: 30 AF XY: 0.0207 AC XY: 14843 AN XY: 716290

Gnomad4 AFR exome AF: 0.0869

Gnomad4 AMR exome AF: 0.0167

Gnomad4 ASJ exome AF: 0.00136

Gnomad4 EAS exome AF: 0.0371

Gnomad4 SAS exome AF: 0.00355

Gnomad4 FIN exome AF: 0.0231

Gnomad4 NFE exome AF: 0.0208

Gnomad4 OTH exome AF: 0.0213

GnomAD4 genome AF: 0.0377 AC: 5736 AN: 152100 Hom.: 175 Cov.: 32 AF XY: 0.0375 AC XY: 2791 AN XY: 74356

Gnomad4 AFR AF: 0.0838

Gnomad4 AMR AF: 0.0288

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0235

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0258

Gnomad4 NFE AF: 0.0191

Gnomad4 OTH AF: 0.0356

Alfa AF: 0.0240 Hom.: 15

Bravo AF: 0.0385

Asia WGS AF: 0.0170 AC: 60 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.9
DANN	Benign	0.45

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: rs17015438; hg19: chr12-88470974;