rs116469117

chr12-88079201-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM5 BP4_Strong BP6_Very_Strong BS1

The NM_025114.4(CEP290):c.5255G>A(p.Arg1752Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000355 in 1,590,584 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1752W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.19

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]

LOC124902977 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-88079202-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 866339.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010704249).
• BP6: Variant 12-88079201-C-T is Benign according to our data. Variant chr12-88079201-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 166833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00189 (285/150446) while in subpopulation AFR AF= 0.00675 (276/40900). AF 95% confidence interval is 0.00609. There are 1 homozygotes in gnomad4. There are 135 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP290	NM_025114.4	c.5255G>A	p.Arg1752Gln	missense_variant	39/54	ENST00000552810.6
LOC124902977	XR_007063393.1	n.887-3112C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP290	ENST00000552810.6	c.5255G>A	p.Arg1752Gln	missense_variant	39/54	1	NM_025114.4	P4

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 285 AN: 150330 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00677

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

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: 0.0000591

Gnomad OTH AF: 0.000968

GnomAD3 exomes AF: 0.000565 AC: 130 AN: 230142 Hom.: 1 AF XY: 0.000423 AC XY: 53 AN XY: 125150

Gnomad AFR exome AF: 0.00834

Gnomad AMR exome AF: 0.000201

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000281

Gnomad OTH exome AF: 0.000370

GnomAD4 exome AF: 0.000194 AC: 280 AN: 1440138 Hom.: 1 Cov.: 31 AF XY: 0.000168 AC XY: 120 AN XY: 715312

Gnomad4 AFR exome AF: 0.00720

Gnomad4 AMR exome AF: 0.000318

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000145

Gnomad4 OTH exome AF: 0.000269

GnomAD4 genome AF: 0.00189 AC: 285 AN: 150446 Hom.: 1 Cov.: 32 AF XY: 0.00184 AC XY: 135 AN XY: 73298

Gnomad4 AFR AF: 0.00675

Gnomad4 AMR AF: 0.000199

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000591

Gnomad4 OTH AF: 0.000958

Alfa AF: 0.000907 Hom.: 0

Bravo AF: 0.00201

ESP6500AA AF: 0.00747 AC: 27

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000704 AC: 85

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2014	- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.77
MVP		0.85
MPC		0.37
ClinPred		0.068	T
GERP RS		5.2
Varity_R		0.32
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs116469117; hg19: chr12-88472978;