NM_025114.4:c.6401T>C

Variant names:

• chr12-88060951-A-G
• rs117852025
• NM_025114.4:c.6401T>C

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.6401T>C​(p.Ile2134Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00731 in 1,562,170 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0053 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (99 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:17
• Conservation: PhyloP100: 8.35
• Publications: 17 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=0.009030223).
• BP6: Variant 12-88060951-A-G is Benign according to our data. Variant chr12-88060951-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166829.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00528 (803/152154) while in subpopulation SAS AF = 0.0137 (66/4818). AF 95% confidence interval is 0.011. There are 7 homozygotes in GnomAd4. There are 382 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.6401T>C	p.Ile2134Thr	missense	Exon 47 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.6401T>C	p.Ile2134Thr	missense	Exon 47 of 54	ENSP00000448012.1	O15078
	CEP290	ENST00000547691.8	TSL:1	c.3683T>C	p.Ile1228Thr	missense	Exon 23 of 28	ENSP00000446905.3	A0A5K1VW81
	CEP290	ENST00000675476.1		c.7262T>C	p.Ile2421Thr	missense	Exon 49 of 56	ENSP00000502161.1	A0A6Q8PGB1

Frequencies

GnomAD3 genomes AF: 0.00528 AC: 802 AN: 152036 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0478

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.000851

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00662

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00758 AC: 1353 AN: 178574 AF XY: 0.00850

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.0407

Gnomad EAS exome AF: 0.0000742

Gnomad FIN exome AF: 0.00105

Gnomad NFE exome AF: 0.00741

Gnomad OTH exome AF: 0.00670

GnomAD4 exome AF: 0.00753 AC: 10614 AN: 1410016 Hom.: 99 Cov.: 31 AF XY: 0.00782 AC XY: 5446 AN XY: 696548

African (AFR) AF: 0.00120 AC: 39 AN: 32406

American (AMR) AF: 0.00241 AC: 89 AN: 36882

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 920 AN: 25378

East Asian (EAS) AF: 0.0000529 AC: 2 AN: 37814

South Asian (SAS) AF: 0.0163 AC: 1284 AN: 78864

European-Finnish (FIN) AF: 0.00111 AC: 56 AN: 50348

Middle Eastern (MID) AF: 0.0163 AC: 93 AN: 5704

European-Non Finnish (NFE) AF: 0.00696 AC: 7544 AN: 1084190

Other (OTH) AF: 0.0100 AC: 587 AN: 58430

GnomAD4 genome AF: 0.00528 AC: 803 AN: 152154 Hom.: 7 Cov.: 32 AF XY: 0.00514 AC XY: 382 AN XY: 74386

African (AFR) AF: 0.00152 AC: 63 AN: 41520

American (AMR) AF: 0.00177 AC: 27 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0478 AC: 166 AN: 3470

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5168

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4818

European-Finnish (FIN) AF: 0.000851 AC: 9 AN: 10582

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00665 AC: 452 AN: 67996

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00714 Hom.: 28

Bravo AF: 0.00506

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000838 AC: 3

ESP6500EA AF: 0.00754 AC: 61

ExAC AF: 0.00543 AC: 639

Asia WGS AF: 0.00347 AC: 12 AN: 3468

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	2	Joubert syndrome 5 (2)
-	-	1	Bardet-Biedl syndrome 14 (1)
-	-	1	Intellectual disability (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	Senior-Loken syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0090	T
MetaSVM	Uncertain	-0.065	T
MutationAssessor	Benign	2.0	M
PhyloP100		8.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.88
MPC		0.38
ClinPred		0.017	T
GERP RS		6.0
Varity_R		0.17
gMVP		0.35
Mutation Taster		=84/16	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: rs117852025; hg19: chr12-88454728; COSMIC: COSV58357095; COSMIC: COSV58357095;