rs11104729

Variant names:

• chr12-88077777-T-C
• rs11104729
• NM_025114.4:c.5506A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025114.4(CEP290):​c.5506A>G​(p.Ile1836Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000801 in 1,580,456 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1836T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (3 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:13
• Conservation: PhyloP100: 0.674
• Publications: 4 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

LOC124902977 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003963411).
• BP6: Variant 12-88077777-T-C is Benign according to our data. Variant chr12-88077777-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261849.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00427 (650/152094) while in subpopulation AFR AF = 0.0149 (619/41570). AF 95% confidence interval is 0.0139. There are 5 homozygotes in GnomAd4. There are 313 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.5506A>G	p.Ile1836Val	missense	Exon 40 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.5506A>G	p.Ile1836Val	missense	Exon 40 of 54	ENSP00000448012.1	O15078
	CEP290	ENST00000547691.8	TSL:1	c.2788A>G	p.Ile930Val	missense	Exon 16 of 28	ENSP00000446905.3	A0A5K1VW81
	CEP290	ENST00000675476.1		c.6367A>G	p.Ile2123Val	missense	Exon 42 of 56	ENSP00000502161.1	A0A6Q8PGB1

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 648 AN: 151978 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00113 AC: 259 AN: 229558 AF XY: 0.000876

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000566

Gnomad OTH exome AF: 0.000360

GnomAD4 exome AF: 0.000431 AC: 616 AN: 1428362 Hom.: 3 Cov.: 28 AF XY: 0.000377 AC XY: 268 AN XY: 710318

African (AFR) AF: 0.0146 AC: 465 AN: 31894

American (AMR) AF: 0.00104 AC: 42 AN: 40356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25578

East Asian (EAS) AF: 0.00 AC: 0 AN: 39030

South Asian (SAS) AF: 0.0000249 AC: 2 AN: 80284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52738

Middle Eastern (MID) AF: 0.00223 AC: 12 AN: 5378

European-Non Finnish (NFE) AF: 0.0000247 AC: 27 AN: 1094046

Other (OTH) AF: 0.00115 AC: 68 AN: 59058

GnomAD4 genome AF: 0.00427 AC: 650 AN: 152094 Hom.: 5 Cov.: 32 AF XY: 0.00421 AC XY: 313 AN XY: 74352

African (AFR) AF: 0.0149 AC: 619 AN: 41570

American (AMR) AF: 0.00131 AC: 20 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00352 AC: 1 AN: 284

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67884

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00182 Hom.: 3

Bravo AF: 0.00457

ESP6500AA AF: 0.0145 AC: 52

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00151 AC: 182

Asia WGS AF: 0.00116 AC: 4 AN: 3450

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	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	Senior-Loken syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.75
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.67
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.095
Sift	Benign	0.31	T
Sift4G	Benign	0.77	T
Polyphen		0.0010	B
Vest4		0.067
MVP		0.28
MPC		0.046
ClinPred		0.0098	T
GERP RS		1.9
Varity_R		0.024
gMVP		0.055
Mutation Taster		=98/2	polymorphism

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: rs11104729; hg19: chr12-88471554;