chr12-88049228-ACT-A

Variant names:

• chr12-88049228-ACT-A
• rs569673313
• NM_025114.4:c.7394_7395delAG

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_Moderate BP6 BS2

The NM_025114.4(CEP290):​c.7394_7395delAG​(p.Glu2465ValfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,604,266 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (5 hom.)
• Consequence: CEP290 NM_025114.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 2.74
• Publications: 1 publications found

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]

RLIG1 (HGNC:25322): (RNA 5'-phosphate and 3'-OH ligase 1) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00618 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 12-88049228-ACT-A is Benign according to our data. Variant chr12-88049228-ACT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372319.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.7394_7395delAG	p.Glu2465ValfsTer2	frameshift_variant	Exon 54 of 54	ENST00000552810.6	NP_079390.3
RLIG1	NM_001009894.3	c.*809_*810delCT		3_prime_UTR_variant	Exon 7 of 7	ENST00000356891.4	NP_001009894.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.7394_7395delAG	p.Glu2465ValfsTer2	frameshift_variant	Exon 54 of 54	1	NM_025114.4	ENSP00000448012.1
RLIG1	ENST00000356891.4	c.*809_*810delCT		3_prime_UTR_variant	Exon 7 of 7	1	NM_001009894.3	ENSP00000349358.3

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151880 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000598 AC: 144 AN: 241004 AF XY: 0.000826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000900

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000323 AC: 469 AN: 1452268 Hom.: 5 AF XY: 0.000452 AC XY: 326 AN XY: 721668

African (AFR) AF: 0.0000302 AC: 1 AN: 33066

American (AMR) AF: 0.000115 AC: 5 AN: 43598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39484

South Asian (SAS) AF: 0.00429 AC: 356 AN: 82954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00191 AC: 8 AN: 4190

European-Non Finnish (NFE) AF: 0.0000631 AC: 70 AN: 1109744

Other (OTH) AF: 0.000484 AC: 29 AN: 59954

GnomAD4 genome AF: 0.000151 AC: 23 AN: 151998 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74312

African (AFR) AF: 0.0000241 AC: 1 AN: 41514

American (AMR) AF: 0.0000655 AC: 1 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000884 AC: 6 AN: 67838

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.0000491

Asia WGS AF: 0.000580 AC: 2 AN: 3462

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Nov 27, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the CEP290 gene. The c.7394_7395delAG variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.7394_7395delAG variant is observed in 72/16,502 (0.4%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.7394_7395delAG variant causes a frameshift starting with codon Glutamic acid 2465, changes this amino acid to a Valine residue and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Glu2465ValfsX2. This variant is predicted to cause loss of normal protein function through protein truncation as the last 15 amino acids of the CEP290 protein and lost and replaced with 1 incorrect amino acid. However, this deletion occurs in a region that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Aug 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CEP290 c.7394_7395delAG (p.Glu2465ValfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00031 in 1604266 control chromosomes, predominantly at a frequency of 0.0042 within the South Asian subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3.76 fold of the estimated maximal expected allele frequency for a pathogenic variant in CEP290 causing Meckel Syndrome Type 4 phenotype (0.0011). c.7394_7395delAG has been reported in the literature in individuals with molecular diagnosis of Joubert syndrome or clinical diagnosis of nonsyndromic retinal dystrophy (Iyer_2022, Testa_2021). Additional patients with retinitis pigmentosa or clinical features of Joubert Syndrome have been reported in the heterozygous state (Bohorquez_2021, Devi_2020), an insufficient genotype. These reports do not provide unequivocal conclusions about association of the variant with Meckel Syndrome Type 4. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34327195, 32139166, 35123515, 22848652, 34196655). ClinVar contains an entry for this variant (Variation ID: 372319). Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CEP290 p.Glu2465Valfs*2 variant was not identified in the literature but was identified in dbSNP (ID: rs569673313) and ClinVar (classified as benign by Invitae; as likely pathogenic by CeGaT Praxis; and as uncertain significance by GeneDx and Shahid Beheshti University of Medical Sciences). The variant was identified in control databases in 144 of 241004 chromosomes (2 homozygous) at a frequency of 0.0005975 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 119 of 28430 chromosomes (freq: 0.004186), European (non-Finnish) in 21 of 108954 chromosomes (freq: 0.000193), Ashkenazi Jewish in 1 of 9878 chromosomes (freq: 0.000101) and Latino in 3 of 33318 chromosomes (freq: 0.00009), but was not observed in the African, East Asian, European (Finnish), or Other populations. The c.7394_7395del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2465 and leads to a premature stop codon at position 2. This variant occurs in the last exon of the CEP290 gene, therefore it is not expected to result in loss of function. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CEP290: BS2 -

CEP290-related disorder Uncertain:1

Sep 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CEP290 c.7394_7395delAG variant is predicted to result in a frameshift and premature protein termination (p.Glu2465Valfs*2). This deletion is near the C-terminus of the CEP290 protein and is predicted to result in a protein that is 12 amino acids shorter than the reference protein. This variant has been reported as a variant of uncertain significance in a large cohort study of patients with obesity (Savas et al. 2019. PubMed ID: 31216558). This variant is reported in 0.42% of alleles in individuals of South Asian descent in gnomAD, including two homozygotes. This population data provides evidence against pathogenicity. However, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Bardet-Biedl syndrome 14 Uncertain:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Uncertain:1

Jan 01, 2021

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 5 Uncertain:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Senior-Loken syndrome 6;C1857780:Joubert syndrome 5;C1857821:Leber congenital amaurosis 10;C1970161:Meckel syndrome, type 4;C2673874:Bardet-Biedl syndrome 14 Benign:1

Mar 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7
Mutation Taster		=167/33	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs569673313; hg19: chr12-88443005;