rs7970228

Variant names:

• chr12-88106775-A-C
• rs7970228
• NM_025114.4:c.2717T>G

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.2717T>G​(p.Leu906Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00756 in 1,610,384 control chromosomes in the GnomAD database, including 713 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (369 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (344 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.79
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016267896).
• BP6: Variant 12-88106775-A-C is Benign according to our data. Variant chr12-88106775-A-C is described in ClinVar as Benign. ClinVar VariationId is 126252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 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.2717T>G	p.Leu906Trp	missense	Exon 25 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.2717T>G	p.Leu906Trp	missense	Exon 25 of 54	ENSP00000448012.1	O15078
	CEP290	ENST00000604024.5	TSL:1	c.1976T>G	p.Leu659Trp	missense	Exon 17 of 20	ENSP00000473863.1	S4R322
	CEP290	ENST00000547691.8	TSL:1	c.-2T>G		5_prime_UTR	Exon 1 of 28	ENSP00000446905.3	A0A5K1VW81

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5980 AN: 152060 Hom.: 369 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00457

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.0321

GnomAD2 exomes AF: 0.0109 AC: 2643 AN: 243360 AF XY: 0.00851

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.00633

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00187

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000274

Gnomad OTH exome AF: 0.00608

GnomAD4 exome AF: 0.00424 AC: 6188 AN: 1458206 Hom.: 344 Cov.: 31 AF XY: 0.00376 AC XY: 2724 AN XY: 725104

African (AFR) AF: 0.138 AC: 4604 AN: 33408

American (AMR) AF: 0.00758 AC: 336 AN: 44310

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26058

East Asian (EAS) AF: 0.000987 AC: 39 AN: 39530

South Asian (SAS) AF: 0.00491 AC: 422 AN: 85880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53008

Middle Eastern (MID) AF: 0.00677 AC: 39 AN: 5760

European-Non Finnish (NFE) AF: 0.000157 AC: 174 AN: 1110018

Other (OTH) AF: 0.00951 AC: 573 AN: 60234

GnomAD4 genome AF: 0.0394 AC: 5992 AN: 152178 Hom.: 369 Cov.: 32 AF XY: 0.0380 AC XY: 2829 AN XY: 74404

African (AFR) AF: 0.135 AC: 5618 AN: 41528

American (AMR) AF: 0.0158 AC: 241 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5180

South Asian (SAS) AF: 0.00457 AC: 22 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 67994

Other (OTH) AF: 0.0318 AC: 67 AN: 2110

Alfa AF: 0.0122 Hom.: 500

Bravo AF: 0.0459

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.124 AC: 452

ESP6500EA AF: 0.000615 AC: 5

ExAC AF: 0.0129 AC: 1550

Asia WGS AF: 0.0100 AC: 35 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	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	Senior-Loken syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.081
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.019	D
Polyphen		0.95	P
Vest4		0.15
MPC		0.28
ClinPred		0.040	T
GERP RS		4.8
PromoterAI		-0.011	Neutral
Varity_R		0.11
gMVP		0.15
Mutation Taster		=299/1	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: rs7970228; hg19: chr12-88500552;