12-88107028-G-T

Variant names:

• chr12-88107028-G-T
• rs886038694
• NM_025114.4:c.2554C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_025114.4(CEP290):​c.2554C>A​(p.Gln852Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,400,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.973
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12144187).
• BP6: Variant 12-88107028-G-T is Benign according to our data. Variant chr12-88107028-G-T is described in ClinVar as [Benign]. Clinvar id is 261838.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4	c.2554C>A	p.Gln852Lys	missense_variant	Exon 24 of 54	ENST00000552810.6	NP_079390.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6	c.2554C>A	p.Gln852Lys	missense_variant	Exon 24 of 54	1	NM_025114.4	ENSP00000448012.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1400340 Hom.: 0 Cov.: 29 AF XY: 0.00000578 AC XY: 4 AN XY: 692046

African (AFR) AF: 0.00 AC: 0 AN: 31392

American (AMR) AF: 0.00 AC: 0 AN: 34376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25202

East Asian (EAS) AF: 0.00 AC: 0 AN: 37354

South Asian (SAS) AF: 0.00 AC: 0 AN: 76982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49688

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5552

European-Non Finnish (NFE) AF: 0.00000370 AC: 4 AN: 1081788

Other (OTH) AF: 0.00 AC: 0 AN: 58006

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.13	.;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;L;.
PhyloP100		0.97
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.33	N;N;.
REVEL	Benign	0.027
Sift	Benign	0.067	T;T;.
Sift4G	Benign	0.073	T;T;T
Polyphen		0.10	.;B;.
Vest4		0.19
MutPred		0.28		.;Gain of ubiquitination at Q852 (P = 0.0101);.;
MVP		0.31
MPC		0.081
ClinPred		0.18	T
GERP RS		3.8
PromoterAI		-0.0075	Neutral
Varity_R		0.10
gMVP		0.13
Mutation Taster		=88/12	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: rs886038694; hg19: chr12-88500805;