12-88139202-A-T

Position:

• chr12-88139202-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_025114.4(CEP290):​c.251-11T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 982,320 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (7 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Scores: Splicing: ADA: 0.09781
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5
• Conservation: PhyloP100: 0.222

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]

CEP290 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-88139202-A-T is Benign according to our data. Variant chr12-88139202-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235736.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=6, Benign=1}. Variant chr12-88139202-A-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP290	NM_025114.4	c.251-11T>A		intron_variant		ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.251-11T>A		intron_variant		1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 298 AN: 150998 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000860

Gnomad ASJ AF: 0.00203

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000583

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.00193

GnomAD3 exomes AF: 0.00167 AC: 125 AN: 74724 Hom.: 1 AF XY: 0.00185 AC XY: 74 AN XY: 40082

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.000477

Gnomad SAS exome AF: 0.000940

Gnomad FIN exome AF: 0.0000764

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00355

GnomAD4 exome AF: 0.00245 AC: 2038 AN: 831218 Hom.: 7 Cov.: 12 AF XY: 0.00246 AC XY: 1035 AN XY: 420310

Gnomad4 AFR exome AF: 0.00124

Gnomad4 AMR exome AF: 0.00191

Gnomad4 ASJ exome AF: 0.00244

Gnomad4 EAS exome AF: 0.00111

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.000367

Gnomad4 NFE exome AF: 0.00281

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00199 AC: 300 AN: 151102 Hom.: 1 Cov.: 33 AF XY: 0.00176 AC XY: 130 AN XY: 73842

Gnomad4 AFR AF: 0.00133

Gnomad4 AMR AF: 0.000859

Gnomad4 ASJ AF: 0.00203

Gnomad4 EAS AF: 0.000968

Gnomad4 SAS AF: 0.00167

Gnomad4 FIN AF: 0.000583

Gnomad4 NFE AF: 0.00294

Gnomad4 OTH AF: 0.00192

Alfa AF: 0.00149 Hom.: 0

Bravo AF: 0.00186

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 14, 2015	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Senior-Loken syndrome 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Leber congenital amaurosis 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Bardet-Biedl syndrome 14 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Meckel syndrome, type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Joubert syndrome 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

CEP290-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 06, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.61
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.098
dbscSNV1_RF	Benign	0.44
SpliceAI score (max)		0.010		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: rs200666995; hg19: chr12-88532979; COSMIC: COSV57123189; COSMIC: COSV57123189;