chr12-88120212-CTTATT-C

Variant names:

• chr12-88120212-CTTATT-C
• rs771266705
• NM_025114.4:c.1419_1423delAATAA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_025114.4(CEP290):​c.1419_1423delAATAA​(p.Ile474ArgfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000735 in 1,360,792 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. K473K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CEP290 NM_025114.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.32
• Publications: 0 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-88120212-CTTATT-C is Pathogenic according to our data. Variant chr12-88120212-CTTATT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 522742.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	NM_025114.4	MANE Select	c.1419_1423delAATAA	p.Ile474ArgfsTer5	frameshift	Exon 15 of 54	NP_079390.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	ENST00000552810.6	TSL:1 MANE Select	c.1419_1423delAATAA	p.Ile474ArgfsTer5	frameshift	Exon 15 of 54	ENSP00000448012.1
	CEP290	ENST00000604024.5	TSL:1	c.585_589delAATAA	p.Ile196ArgfsTer5	frameshift	Exon 6 of 20	ENSP00000473863.1
	CEP290	ENST00000547926.7	TSL:1	n.1419_1423delAATAA		non_coding_transcript_exon	Exon 15 of 21	ENSP00000448573.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000666 AC: 1 AN: 150048 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000246

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1360792 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 672380

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

African (AFR) AF: 0.00 AC: 0 AN: 30022

American (AMR) AF: 0.00 AC: 0 AN: 31372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24616

East Asian (EAS) AF: 0.00 AC: 0 AN: 35526

South Asian (SAS) AF: 0.00 AC: 0 AN: 71504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4954

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1057068

Other (OTH) AF: 0.0000177 AC: 1 AN: 56410

⚠️ 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: 0.0000509 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Bardet-Biedl syndrome 14 (2)
2	-	-	not provided (2)
1	-	-	CEP290-related ciliopathy (1)
1	-	-	Leber congenital amaurosis (1)
1	-	-	Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis (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		5.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs771266705; hg19: chr12-88513989;