rs115837670

Positions:

• chr12-88109218-A-C

Variant summary

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

The NM_025114.4(CEP290):​c.2368-37T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 677,942 control chromosomes in the GnomAD database, including 320 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (140 hom., cov: 32)
  • Exomes 𝑓: 0.021 (180 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0850

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-88109218-A-C is Benign according to our data. Variant chr12-88109218-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 126250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4	c.2368-37T>G		intron_variant		ENST00000552810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6	c.2368-37T>G		intron_variant		1	NM_025114.4	P4

Frequencies

GnomAD3 genomes AF: 0.0347 AC: 5276 AN: 152050 Hom.: 139 Cov.: 32

Gnomad AFR AF: 0.0729

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0279

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0193

Gnomad OTH AF: 0.0363

GnomAD3 exomes AF: 0.0184 AC: 1379 AN: 75044 Hom.: 22 AF XY: 0.0165 AC XY: 684 AN XY: 41520

Gnomad AFR exome AF: 0.0675

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.00165

Gnomad EAS exome AF: 0.0135

Gnomad SAS exome AF: 0.00337

Gnomad FIN exome AF: 0.0253

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0209 AC: 11006 AN: 525774 Hom.: 180 Cov.: 7 AF XY: 0.0197 AC XY: 5545 AN XY: 282142

Gnomad4 AFR exome AF: 0.0730

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.00232

Gnomad4 EAS exome AF: 0.0466

Gnomad4 SAS exome AF: 0.00368

Gnomad4 FIN exome AF: 0.0234

Gnomad4 NFE exome AF: 0.0202

Gnomad4 OTH exome AF: 0.0224

GnomAD4 genome AF: 0.0348 AC: 5289 AN: 152168 Hom.: 140 Cov.: 32 AF XY: 0.0347 AC XY: 2583 AN XY: 74400

Gnomad4 AFR AF: 0.0730

Gnomad4 AMR AF: 0.0279

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.0232

Gnomad4 SAS AF: 0.00312

Gnomad4 FIN AF: 0.0258

Gnomad4 NFE AF: 0.0193

Gnomad4 OTH AF: 0.0359

Alfa AF: 0.0229 Hom.: 19

Bravo AF: 0.0352

Asia WGS AF: 0.0160 AC: 54 AN: 3462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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

not provided Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.35

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: rs115837670; hg19: chr12-88502995;