Genetic Variant NM_025114.4:c.7423A>T (chr12-88049201-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025114.4(CEP290):c.7423A>T(p.Asn2475Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CEP290
NM_025114.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.118

Variant links:

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 links:

RLIG1 (HGNC:25322): (RNA 5'-phosphate and 3'-OH ligase 1) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. [provided by Alliance of Genome Resources, Apr 2022]

RLIG1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2113998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP290	NM_025114.4 link	c.7423A>T	p.Asn2475Tyr	missense_variant	Exon 54 of 54	ENST00000552810.6	NP_079390.3	O15078Q05BJ6
RLIG1	NM_001009894.3 link	c.*779T>A		3_prime_UTR_variant	Exon 7 of 7	ENST00000356891.4	NP_001009894.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP290	ENST00000552810.6 link	c.7423A>T	p.Asn2475Tyr	missense_variant	Exon 54 of 54	1	NM_025114.4	ENSP00000448012.1		O15078
C12orf29	ENST00000356891.4 link	c.*779T>A		3_prime_UTR_variant	Exon 7 of 7	1	NM_001009894.3	ENSP00000349358.3		Q8N999-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441052

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716012

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.091

.;.;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.68

T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.90

.;.;L

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.18

N;N;N

REVEL

Benign

0.090

Sift

Uncertain

0.013

D;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

0.40

.;.;B

Vest4

0.46

MutPred

0.22

.;.;Gain of catalytic residue at Y2479 (P = 0.0121);

MVP

0.69

MPC

0.13

ClinPred

0.73

GERP RS

2.8

Varity_R

0.048

gMVP

0.32

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over