12-88055666-AT-ATT

Variant names:

• chr12-88055666-A-AT
• rs587783017
• NM_025114.4:c.6869dupA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_025114.4(CEP290):​c.6869dupA​(p.Asn2290LysfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,401,328 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N2290N) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: CEP290 NM_025114.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 1.64
• Publications: 8 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]

CEP290 Gene-Disease associations (from GenCC):

• CEP290-related ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Bardet-Biedl syndrome 14

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Leber congenital amaurosis 10

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000299515 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 12-88055666-A-AT is Pathogenic according to our data. Variant chr12-88055666-A-AT is described in ClinVar as Pathogenic. ClinVar VariationId is 156386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025114.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	NM_025114.4	MANE Select	c.6869dupA	p.Asn2290LysfsTer6	frameshift	Exon 50 of 54	NP_079390.3	O15078

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	ENST00000552810.6	TSL:1 MANE Select	c.6869dupA	p.Asn2290LysfsTer6	frameshift	Exon 50 of 54	ENSP00000448012.1	O15078
	CEP290	ENST00000547691.8	TSL:1	c.3928-1254dupA		intron	N/A	ENSP00000446905.3	A0A5K1VW81
	CEP290	ENST00000675476.1		c.7730dupA	p.Asn2577LysfsTer6	frameshift	Exon 52 of 56	ENSP00000502161.1	A0A6Q8PGB1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000272 AC: 44 AN: 161872 AF XY: 0.000313

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000257

Gnomad FIN exome AF: 0.0000549

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000621 AC: 87 AN: 1401328 Hom.: 0 Cov.: 29 AF XY: 0.0000895 AC XY: 62 AN XY: 692712

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000127 AC: 4 AN: 31618

American (AMR) AF: 0.000205 AC: 7 AN: 34120

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25108

East Asian (EAS) AF: 0.0000527 AC: 2 AN: 37960

South Asian (SAS) AF: 0.000658 AC: 50 AN: 76016

European-Finnish (FIN) AF: 0.0000197 AC: 1 AN: 50876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.0000185 AC: 20 AN: 1081744

Other (OTH) AF: 0.0000343 AC: 2 AN: 58230

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.000217 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	CEP290-related disorder (3)
2	-	-	not provided (2)
1	-	-	Bardet-Biedl syndrome 14 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Leber congenital amaurosis (1)
1	-	-	Leber congenital amaurosis 10 (1)
1	-	-	Meckel-Gruber syndrome;C0687120:Nephronophthisis;C5979921:Joubert syndrome (1)
1	-	-	Retinal dystrophy (1)
1	-	-	Senior-Loken syndrome 6;C1857780:Joubert syndrome 5;C1857821:Leber congenital amaurosis 10;C1970161:Meckel syndrome, type 4;C2673874:Bardet-Biedl syndrome 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=0/200	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587783017;

hg19: chr12-88449443;