rs199770158

chr12-88126442-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_025114.4(CEP290):c.943-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00029 in 1,480,450 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: CEP290 NM_025114.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006957
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3 O:1
• Conservation: PhyloP100: 0.202

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-88126442-G-A is Benign according to our data. Variant chr12-88126442-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252747.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4	c.943-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000552810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6	c.943-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_025114.4	P4

Frequencies

GnomAD3 genomes AF: 0.000356 AC: 54 AN: 151846 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000589

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000285 AC: 46 AN: 161474 Hom.: 0 AF XY: 0.000246 AC XY: 22 AN XY: 89324

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000172

Gnomad FIN exome AF: 0.000101

Gnomad NFE exome AF: 0.000497

Gnomad OTH exome AF: 0.000285

GnomAD4 exome AF: 0.000282 AC: 375 AN: 1328486 Hom.: 1 Cov.: 24 AF XY: 0.000306 AC XY: 202 AN XY: 659504

Gnomad4 AFR exome AF: 0.0000375

Gnomad4 AMR exome AF: 0.000206

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000152

Gnomad4 FIN exome AF: 0.0000962

Gnomad4 NFE exome AF: 0.000328

Gnomad4 OTH exome AF: 0.000218

GnomAD4 genome AF: 0.000355 AC: 54 AN: 151964 Hom.: 0 Cov.: 33 AF XY: 0.000350 AC XY: 26 AN XY: 74274

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.000589

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000551 Hom.: 0

Bravo AF: 0.000302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CEP290: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Nov 16, 2015

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2021

The c.943-4C>T intronic alteration consists of a C to T substitution 4 nucleotides before coding exon 11 in the CEP290 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

CEP290-related ciliopathies Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	12
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000070
dbscSNV1_RF	Benign	0.012
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: rs199770158; hg19: chr12-88520219;