12-88059831-C-T

Variant names:

• chr12-88059831-C-T
• rs2471512
• NM_025114.4:c.6645+67G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025114.4(CEP290):​c.6645+67G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.944 in 1,324,504 control chromosomes in the GnomAD database, including 590,700 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (65636 hom., cov: 33)
  • Exomes 𝑓: 0.95 (525064 hom.)
• Consequence: CEP290 NM_025114.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0210
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 12-88059831-C-T is Benign according to our data. Variant chr12-88059831-C-T is described in ClinVar as Benign. ClinVar VariationId is 1209819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	NM_025114.4	MANE Select	c.6645+67G>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.6645+67G>A		intron	N/A	ENSP00000448012.1
	CEP290	ENST00000547691.8	TSL:1	c.3927+67G>A		intron	N/A	ENSP00000446905.3
	CEP290	ENST00000675476.1		c.7506+67G>A		intron	N/A	ENSP00000502161.1

Frequencies

GnomAD3 genomes AF: 0.928 AC: 141164 AN: 152148 Hom.: 65602 Cov.: 33

Gnomad AFR AF: 0.873

Gnomad AMI AF: 0.953

Gnomad AMR AF: 0.938

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.987

Gnomad SAS AF: 0.905

Gnomad FIN AF: 0.988

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.948

Gnomad OTH AF: 0.932

GnomAD4 exome AF: 0.946 AC: 1109143 AN: 1172238 Hom.: 525064 AF XY: 0.945 AC XY: 551611 AN XY: 583818

African (AFR) AF: 0.873 AC: 21897 AN: 25092

American (AMR) AF: 0.954 AC: 20281 AN: 21264

Ashkenazi Jewish (ASJ) AF: 0.907 AC: 18368 AN: 20260

East Asian (EAS) AF: 0.992 AC: 34770 AN: 35064

South Asian (SAS) AF: 0.904 AC: 55644 AN: 61586

European-Finnish (FIN) AF: 0.984 AC: 44646 AN: 45368

Middle Eastern (MID) AF: 0.916 AC: 3790 AN: 4136

European-Non Finnish (NFE) AF: 0.949 AC: 863228 AN: 909766

Other (OTH) AF: 0.936 AC: 46519 AN: 49702

GnomAD4 genome AF: 0.928 AC: 141252 AN: 152266 Hom.: 65636 Cov.: 33 AF XY: 0.930 AC XY: 69224 AN XY: 74436

African (AFR) AF: 0.872 AC: 36224 AN: 41530

American (AMR) AF: 0.938 AC: 14346 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 3109 AN: 3472

East Asian (EAS) AF: 0.987 AC: 5104 AN: 5170

South Asian (SAS) AF: 0.906 AC: 4371 AN: 4824

European-Finnish (FIN) AF: 0.988 AC: 10483 AN: 10606

Middle Eastern (MID) AF: 0.946 AC: 278 AN: 294

European-Non Finnish (NFE) AF: 0.948 AC: 64495 AN: 68040

Other (OTH) AF: 0.932 AC: 1973 AN: 2116

Alfa AF: 0.938 Hom.: 80652

Bravo AF: 0.923

Asia WGS AF: 0.928 AC: 3228 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Bardet-Biedl syndrome 14 (1)
-	-	1	Joubert syndrome 5 (1)
-	-	1	Meckel syndrome, type 4 (1)
-	-	1	Senior-Loken syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	6.4
DANN	Benign	0.50
PhyloP100		0.021
Mutation Taster		=100/0	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: rs2471512; hg19: chr12-88453608;