rs150138016

Variant names:

• chr12-88090836-C-T
• rs150138016
• NM_025114.4:c.3465G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_025114.4(CEP290):​c.3465G>A​(p.Leu1155Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,539,792 control chromosomes in the GnomAD database, including 34 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 0.0075 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (15 hom.)
• Consequence: CEP290 NM_025114.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: -0.0590
• Publications: 2 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 12-88090836-C-T is Benign according to our data. Variant chr12-88090836-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 136729.
• BP7: Synonymous conserved (PhyloP=-0.059 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00751 (1143/152282) while in subpopulation AFR AF = 0.0264 (1097/41560). AF 95% confidence interval is 0.0251. There are 19 homozygotes in GnomAd4. There are 573 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	NM_025114.4	MANE Select	c.3465G>A	p.Leu1155Leu	synonymous	Exon 30 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.3465G>A	p.Leu1155Leu	synonymous	Exon 30 of 54	ENSP00000448012.1	O15078
	CEP290	ENST00000547691.8	TSL:1	c.747G>A	p.Leu249Leu	synonymous	Exon 6 of 28	ENSP00000446905.3	A0A5K1VW81
	CEP290	ENST00000675476.1		c.4326G>A	p.Leu1442Leu	synonymous	Exon 32 of 56	ENSP00000502161.1	A0A6Q8PGB1

Frequencies

GnomAD3 genomes AF: 0.00752 AC: 1144 AN: 152164 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00168 AC: 273 AN: 162686 AF XY: 0.00124

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.00201

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: 0.00

GnomAD4 exome AF: 0.000743 AC: 1031 AN: 1387510 Hom.: 15 Cov.: 25 AF XY: 0.000639 AC XY: 438 AN XY: 685742

African (AFR) AF: 0.0266 AC: 845 AN: 31716

American (AMR) AF: 0.00187 AC: 67 AN: 35790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25126

East Asian (EAS) AF: 0.0000273 AC: 1 AN: 36662

South Asian (SAS) AF: 0.0000507 AC: 4 AN: 78866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49158

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5662

European-Non Finnish (NFE) AF: 0.0000234 AC: 25 AN: 1066794

Other (OTH) AF: 0.00152 AC: 88 AN: 57736

GnomAD4 genome AF: 0.00751 AC: 1143 AN: 152282 Hom.: 19 Cov.: 32 AF XY: 0.00769 AC XY: 573 AN XY: 74468

African (AFR) AF: 0.0264 AC: 1097 AN: 41560

American (AMR) AF: 0.00242 AC: 37 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00493 Hom.: 5

Bravo AF: 0.00840

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Bardet-Biedl syndrome 14 (1)
-	-	1	Joubert syndrome 5 (1)
-	1	-	Kidney disorder (1)
-	-	1	Leber congenital amaurosis (1)
-	1	-	Leber congenital amaurosis 10 (1)
-	-	1	Meckel syndrome, type 4 (1)
-	-	1	Meckel-Gruber syndrome;C0687120:Nephronophthisis;C5979921:Joubert syndrome (1)
-	-	1	not provided (1)
-	-	1	Senior-Loken syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.7
DANN	Benign	0.69
PhyloP100		-0.059
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs150138016; hg19: chr12-88484613;