rs377613416

Positions:

• chr12-88064134-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_025114.4(CEP290):​c.6136-19T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,520,118 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00048 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (1 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.470

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-88064134-A-C is Benign according to our data. Variant chr12-88064134-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 261850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-88064134-A-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP290	NM_025114.4	c.6136-19T>G		intron_variant		ENST00000552810.6	NP_079390.3
LOC124902977	XR_007063393.1	n.886+7114A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.6136-19T>G		intron_variant		1	NM_025114.4	ENSP00000448012	P4

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152124 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000424 AC: 59 AN: 139076 Hom.: 0 AF XY: 0.000408 AC XY: 30 AN XY: 73446

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000406

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000845

Gnomad OTH exome AF: 0.000257

GnomAD4 exome AF: 0.000814 AC: 1114 AN: 1367994 Hom.: 1 Cov.: 26 AF XY: 0.000834 AC XY: 563 AN XY: 674714

Gnomad4 AFR exome AF: 0.000134

Gnomad4 AMR exome AF: 0.000100

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000695

Gnomad4 FIN exome AF: 0.0000204

Gnomad4 NFE exome AF: 0.000971

Gnomad4 OTH exome AF: 0.000370

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152124 Hom.: 1 Cov.: 32 AF XY: 0.000404 AC XY: 30 AN XY: 74298

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000912

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000812 Hom.: 0

Bravo AF: 0.000544

Asia WGS AF: 0.000290 AC: 1 AN: 3466

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2016	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. -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	11
DANN	Benign	0.55

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: rs377613416; hg19: chr12-88457911;