12-88079134-G-A

Variant names:

• chr12-88079134-G-A
• rs117370446
• NM_025114.4:c.5322C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The ENST00000552810.6(CEP290):​c.5322C>T​(p.Leu1774Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,597,012 control chromosomes in the GnomAD database, including 18 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 0.0033 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (14 hom.)
• Consequence: CEP290 ENST00000552810.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:17
• Conservation: PhyloP100: 1.57
• 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

LOC124902977 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 12-88079134-G-A is Benign according to our data. Variant chr12-88079134-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197085.
• BP7: Synonymous conserved (PhyloP=1.57 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000552810.6. 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.5322C>T	p.Leu1774Leu	synonymous	Exon 39 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.5322C>T	p.Leu1774Leu	synonymous	Exon 39 of 54	ENSP00000448012.1
	CEP290	ENST00000547691.8	TSL:1	c.2604C>T	p.Leu868Leu	synonymous	Exon 15 of 28	ENSP00000446905.3
	CEP290	ENST00000675476.1		c.6183C>T	p.Leu2061Leu	synonymous	Exon 41 of 56	ENSP00000502161.1

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 510 AN: 151992 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.00544

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00437

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00352 AC: 825 AN: 234650 AF XY: 0.00341

Gnomad AFR exome AF: 0.000419

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.0000605

Gnomad FIN exome AF: 0.00178

Gnomad NFE exome AF: 0.00447

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00375 AC: 5418 AN: 1444902 Hom.: 14 Cov.: 31 AF XY: 0.00375 AC XY: 2692 AN XY: 718130

African (AFR) AF: 0.000615 AC: 20 AN: 32532

American (AMR) AF: 0.00366 AC: 153 AN: 41858

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 339 AN: 25890

East Asian (EAS) AF: 0.00 AC: 0 AN: 38440

South Asian (SAS) AF: 0.00149 AC: 123 AN: 82364

European-Finnish (FIN) AF: 0.00216 AC: 115 AN: 53124

Middle Eastern (MID) AF: 0.00926 AC: 53 AN: 5726

European-Non Finnish (NFE) AF: 0.00395 AC: 4371 AN: 1105320

Other (OTH) AF: 0.00409 AC: 244 AN: 59648

GnomAD4 genome AF: 0.00335 AC: 509 AN: 152110 Hom.: 4 Cov.: 32 AF XY: 0.00336 AC XY: 250 AN XY: 74362

African (AFR) AF: 0.000434 AC: 18 AN: 41498

American (AMR) AF: 0.00544 AC: 83 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4818

European-Finnish (FIN) AF: 0.00236 AC: 25 AN: 10572

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00437 AC: 297 AN: 67998

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00364 Hom.: 2

Bravo AF: 0.00367

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	2	Joubert syndrome 5 (2)
-	-	1	Bardet-Biedl syndrome 14 (1)
-	-	1	CEP290-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Leber congenital amaurosis (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	-0.47
CADD	Benign	9.5
DANN	Benign	0.69
PhyloP100		1.6
Mutation Taster		=97/3	polymorphism

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: rs117370446; hg19: chr12-88472911;