rs45465996

Variant names:

• chr12-88111856-A-G
• rs45465996
• NM_025114.4:c.2055T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_025114.4(CEP290):​c.2055T>C​(p.Ala685Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,560,026 control chromosomes in the GnomAD database, including 20,067 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1389 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18678 hom.)
• Consequence: CEP290 NM_025114.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 0.00200
• Publications: 11 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.058).
• BP6: Variant 12-88111856-A-G is Benign according to our data. Variant chr12-88111856-A-G is described in ClinVar as Benign. ClinVar VariationId is 96168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.002 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

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.2055T>C	p.Ala685Ala	splice_region synonymous	Exon 21 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.2055T>C	p.Ala685Ala	splice_region synonymous	Exon 21 of 54	ENSP00000448012.1	O15078
	CEP290	ENST00000604024.5	TSL:1	c.1314T>C	p.Ala438Ala	splice_region synonymous	Exon 13 of 20	ENSP00000473863.1	S4R322
	CEP290	ENST00000547926.7	TSL:1	n.1912T>C		splice_region non_coding_transcript_exon	Exon 20 of 21	ENSP00000448573.3	F8VS29

Frequencies

GnomAD3 genomes AF: 0.118 AC: 18003 AN: 151982 Hom.: 1390 Cov.: 32

Gnomad AFR AF: 0.0401

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0544

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.154

GnomAD2 exomes AF: 0.138 AC: 26048 AN: 188434 AF XY: 0.141

Gnomad AFR exome AF: 0.0417

Gnomad AMR exome AF: 0.0959

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.0000813

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.156 AC: 219449 AN: 1407926 Hom.: 18678 Cov.: 29 AF XY: 0.155 AC XY: 108124 AN XY: 698092

African (AFR) AF: 0.0408 AC: 1250 AN: 30618

American (AMR) AF: 0.0977 AC: 3585 AN: 36676

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 5524 AN: 25164

East Asian (EAS) AF: 0.000163 AC: 6 AN: 36830

South Asian (SAS) AF: 0.0653 AC: 4988 AN: 76432

European-Finnish (FIN) AF: 0.121 AC: 6233 AN: 51644

Middle Eastern (MID) AF: 0.255 AC: 1437 AN: 5646

European-Non Finnish (NFE) AF: 0.173 AC: 187607 AN: 1086810

Other (OTH) AF: 0.152 AC: 8819 AN: 58106

GnomAD4 genome AF: 0.118 AC: 17991 AN: 152100 Hom.: 1389 Cov.: 32 AF XY: 0.115 AC XY: 8527 AN XY: 74374

African (AFR) AF: 0.0399 AC: 1658 AN: 41548

American (AMR) AF: 0.115 AC: 1752 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 701 AN: 3468

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.0542 AC: 262 AN: 4830

European-Finnish (FIN) AF: 0.121 AC: 1277 AN: 10566

Middle Eastern (MID) AF: 0.315 AC: 92 AN: 292

European-Non Finnish (NFE) AF: 0.173 AC: 11776 AN: 67924

Other (OTH) AF: 0.152 AC: 320 AN: 2108

Alfa AF: 0.145 Hom.: 1634

Bravo AF: 0.118

Asia WGS AF: 0.0300 AC: 104 AN: 3466

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (3)
-	-	1	Bardet-Biedl syndrome 14 (1)
-	-	1	Joubert syndrome 5 (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	Retinal dystrophy (1)
-	-	1	Senior-Loken syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	11
DANN	Uncertain	0.99
PhyloP100		0.0020
Mutation Taster		=80/20	polymorphism (auto)

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: rs45465996; hg19: chr12-88505633; COSMIC: COSV58351509;