12-88087872-C-T

Variant names:

• chr12-88087872-C-T
• rs184143186
• NM_025114.4:c.4102G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_025114.4(CEP290):​c.4102G>A​(p.Asp1368Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000266 in 1,239,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. D1368H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 3.88
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011195302).
• BP6: Variant 12-88087872-C-T is Benign according to our data. Variant chr12-88087872-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196795.

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.4102G>A	p.Asp1368Asn	missense	Exon 32 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.4102G>A	p.Asp1368Asn	missense	Exon 32 of 54	ENSP00000448012.1	O15078
	CEP290	ENST00000547691.8	TSL:1	c.1384G>A	p.Asp462Asn	missense	Exon 8 of 28	ENSP00000446905.3	A0A5K1VW81
	CEP290	ENST00000675476.1		c.4963G>A	p.Asp1655Asn	missense	Exon 34 of 56	ENSP00000502161.1	A0A6Q8PGB1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 191 AN: 151882 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00423

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000170 AC: 8 AN: 47106 AF XY: 0.0000413

Gnomad AFR exome AF: 0.00285

Gnomad AMR exome AF: 0.000835

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000128 AC: 139 AN: 1087458 Hom.: 0 Cov.: 18 AF XY: 0.000111 AC XY: 58 AN XY: 522218

African (AFR) AF: 0.00571 AC: 128 AN: 22422

American (AMR) AF: 0.000212 AC: 2 AN: 9452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16094

East Asian (EAS) AF: 0.00 AC: 0 AN: 26944

South Asian (SAS) AF: 0.00 AC: 0 AN: 26542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4596

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 898498

Other (OTH) AF: 0.000205 AC: 9 AN: 43944

GnomAD4 genome AF: 0.00126 AC: 191 AN: 152000 Hom.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74300

African (AFR) AF: 0.00422 AC: 175 AN: 41478

American (AMR) AF: 0.000721 AC: 11 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67966

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.000661 Hom.: 2

Bravo AF: 0.00158

ESP6500AA AF: 0.00316 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000214 AC: 21

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	Leber congenital amaurosis (1)
-	-	1	Meckel-Gruber syndrome;C0687120:Nephronophthisis;C5979921:Joubert syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.020
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.059
Sift	Benign	0.42	T
Sift4G	Benign	0.41	T
Polyphen		0.33	B
Vest4		0.25
MVP		0.71
MPC		0.084
ClinPred		0.021	T
GERP RS		5.5
Varity_R		0.047
gMVP		0.16
Mutation Taster		=96/4	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: rs184143186; hg19: chr12-88481649;