12-88139202-A-T

Variant names:

• chr12-88139202-A-T
• rs200666995
• NM_025114.4:c.251-11T>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_025114.4(CEP290):​c.251-11T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 982,320 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (7 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Scores: Splicing: ADA: 0.09781
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5
• Conservation: PhyloP100: 0.222
• 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]

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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-88139202-A-T is Benign according to our data. Variant chr12-88139202-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235736.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR,AD gene

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.251-11T>A		intron	N/A	NP_079390.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	ENST00000552810.6	TSL:1 MANE Select	c.251-11T>A		intron	N/A	ENSP00000448012.1
	CEP290	ENST00000547926.7	TSL:1	n.251-11T>A		intron	N/A	ENSP00000448573.3
	CEP290	ENST00000675476.1		c.251-11T>A		intron	N/A	ENSP00000502161.1

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 298 AN: 150998 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000860

Gnomad ASJ AF: 0.00203

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000583

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.00193

GnomAD2 exomes AF: 0.00167 AC: 125 AN: 74724 AF XY: 0.00185

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.000477

Gnomad FIN exome AF: 0.0000764

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00355

GnomAD4 exome AF: 0.00245 AC: 2038 AN: 831218 Hom.: 7 Cov.: 12 AF XY: 0.00246 AC XY: 1035 AN XY: 420310

African (AFR) AF: 0.00124 AC: 22 AN: 17728

American (AMR) AF: 0.00191 AC: 27 AN: 14138

Ashkenazi Jewish (ASJ) AF: 0.00244 AC: 40 AN: 16364

East Asian (EAS) AF: 0.00111 AC: 31 AN: 27930

South Asian (SAS) AF: 0.00110 AC: 51 AN: 46360

European-Finnish (FIN) AF: 0.000367 AC: 15 AN: 40910

Middle Eastern (MID) AF: 0.00243 AC: 10 AN: 4114

European-Non Finnish (NFE) AF: 0.00281 AC: 1764 AN: 627180

Other (OTH) AF: 0.00214 AC: 78 AN: 36494

GnomAD4 genome AF: 0.00199 AC: 300 AN: 151102 Hom.: 1 Cov.: 33 AF XY: 0.00176 AC XY: 130 AN XY: 73842

African (AFR) AF: 0.00133 AC: 55 AN: 41304

American (AMR) AF: 0.000859 AC: 13 AN: 15142

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 7 AN: 3448

East Asian (EAS) AF: 0.000968 AC: 5 AN: 5166

South Asian (SAS) AF: 0.00167 AC: 8 AN: 4804

European-Finnish (FIN) AF: 0.000583 AC: 6 AN: 10290

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00294 AC: 199 AN: 67662

Other (OTH) AF: 0.00192 AC: 4 AN: 2084

Alfa AF: 0.00149 Hom.: 0

Bravo AF: 0.00186

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	2	not specified (2)
-	1	-	Bardet-Biedl syndrome 14 (1)
-	-	1	CEP290-related disorder (1)
-	1	-	Joubert syndrome 5 (1)
-	1	-	Leber congenital amaurosis 10 (1)
-	1	-	Meckel syndrome, type 4 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis (1)
-	1	-	Senior-Loken syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.61
DANN	Benign	0.41
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.098
dbscSNV1_RF	Benign	0.44
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

Other links and lift over

dbSNP: rs200666995; hg19: chr12-88532979; COSMIC: COSV57123189; COSMIC: COSV57123189;