rs11104738

Variant names:

• chr12-88107070-T-C
• rs11104738
• NM_025114.4:c.2512A>G

Variant summary

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

The ENST00000552810.6(CEP290):​c.2512A>G​(p.Lys838Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 1,548,946 control chromosomes in the GnomAD database, including 4,606 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 0.057 (473 hom., cov: 32)
  • Exomes 𝑓: 0.059 (4133 hom.)
• Consequence: CEP290 ENST00000552810.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 2.96
• Publications: 25 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015718639).
• BP6: Variant 12-88107070-T-C is Benign according to our data. Variant chr12-88107070-T-C is described in ClinVar as Benign. ClinVar VariationId is 100593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

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.2512A>G	p.Lys838Glu	missense	Exon 24 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.2512A>G	p.Lys838Glu	missense	Exon 24 of 54	ENSP00000448012.1
	CEP290	ENST00000604024.5	TSL:1	c.1771A>G	p.Lys591Glu	missense	Exon 16 of 20	ENSP00000473863.1
	CEP290	ENST00000675476.1		c.3373A>G	p.Lys1125Glu	missense	Exon 26 of 56	ENSP00000502161.1

Frequencies

GnomAD3 genomes AF: 0.0570 AC: 8670 AN: 152090 Hom.: 470 Cov.: 32

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.0935

Gnomad FIN AF: 0.0972

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0421

Gnomad OTH AF: 0.0617

GnomAD2 exomes AF: 0.0788 AC: 13134 AN: 166650 AF XY: 0.0758

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.0345

Gnomad EAS exome AF: 0.213

Gnomad FIN exome AF: 0.0921

Gnomad NFE exome AF: 0.0411

Gnomad OTH exome AF: 0.0669

GnomAD4 exome AF: 0.0588 AC: 82172 AN: 1396738 Hom.: 4133 Cov.: 29 AF XY: 0.0588 AC XY: 40568 AN XY: 689896

African (AFR) AF: 0.0157 AC: 495 AN: 31564

American (AMR) AF: 0.152 AC: 5182 AN: 34120

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 907 AN: 25212

East Asian (EAS) AF: 0.296 AC: 11001 AN: 37164

South Asian (SAS) AF: 0.0837 AC: 6441 AN: 76982

European-Finnish (FIN) AF: 0.0850 AC: 4173 AN: 49096

Middle Eastern (MID) AF: 0.0190 AC: 98 AN: 5150

European-Non Finnish (NFE) AF: 0.0465 AC: 50180 AN: 1079552

Other (OTH) AF: 0.0638 AC: 3695 AN: 57898

GnomAD4 genome AF: 0.0569 AC: 8668 AN: 152208 Hom.: 473 Cov.: 32 AF XY: 0.0619 AC XY: 4603 AN XY: 74406

African (AFR) AF: 0.0184 AC: 764 AN: 41548

American (AMR) AF: 0.133 AC: 2037 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3472

East Asian (EAS) AF: 0.228 AC: 1180 AN: 5176

South Asian (SAS) AF: 0.0917 AC: 443 AN: 4830

European-Finnish (FIN) AF: 0.0972 AC: 1029 AN: 10590

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0420 AC: 2859 AN: 67994

Other (OTH) AF: 0.0610 AC: 129 AN: 2114

Alfa AF: 0.0494 Hom.: 869

Bravo AF: 0.0595

TwinsUK AF: 0.0418 AC: 155

ALSPAC AF: 0.0451 AC: 174

ESP6500AA AF: 0.0157 AC: 56

ESP6500EA AF: 0.0401 AC: 324

ExAC AF: 0.0532 AC: 6037

Asia WGS AF: 0.173 AC: 598 AN: 3462

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Bardet-Biedl syndrome 14 (1)
-	-	1	Joubert syndrome 1 (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;C0431399:Joubert syndrome;C0687120:Nephronophthisis (1)
-	-	1	not provided (2)
-	-	1	Retinal dystrophy (1)
-	-	1	Senior-Loken syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Benign	0.21
DEOGEN2	Benign	0.080	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.4	N
PhyloP100		3.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.020
MPC		0.067
ClinPred		0.00073	T
GERP RS		4.8
PromoterAI		0.019	Neutral
Varity_R		0.077
gMVP		0.042
Mutation Taster		=288/12	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: rs11104738; hg19: chr12-88500847; COSMIC: COSV58350746; COSMIC: COSV58350746;