rs147626659

chr12-88102799-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025114.4(CEP290):c.2991+39A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00584 in 1,555,368 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (32 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0170

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=-0.83).
• BP6: Variant 12-88102799-T-C is Benign according to our data. Variant chr12-88102799-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 261842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88102799-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00523 (796/152146) while in subpopulation AMR AF= 0.00929 (142/15282). AF 95% confidence interval is 0.00805. There are 7 homozygotes in gnomad4. There are 381 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.2991+39A>G		intron_variant		ENST00000552810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6	c.2991+39A>G		intron_variant		1	NM_025114.4	P4

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 797 AN: 152028 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00930

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00576

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00730

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00469 AC: 1007 AN: 214858 Hom.: 7 AF XY: 0.00457 AC XY: 534 AN XY: 116952

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00631

Gnomad ASJ exome AF: 0.000468

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00568

Gnomad NFE exome AF: 0.00673

Gnomad OTH exome AF: 0.00562

GnomAD4 exome AF: 0.00590 AC: 8280 AN: 1403222 Hom.: 32 Cov.: 26 AF XY: 0.00572 AC XY: 3982 AN XY: 696278

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00622

Gnomad4 ASJ exome AF: 0.000447

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000644

Gnomad4 FIN exome AF: 0.00573

Gnomad4 NFE exome AF: 0.00686

Gnomad4 OTH exome AF: 0.00503

GnomAD4 genome AF: 0.00523 AC: 796 AN: 152146 Hom.: 7 Cov.: 32 AF XY: 0.00512 AC XY: 381 AN XY: 74386

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00929

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00576

Gnomad4 NFE AF: 0.00728

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00547 Hom.: 1

Bravo AF: 0.00507

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 19, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.80
Dann	Benign	0.70

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: rs147626659; hg19: chr12-88496576;