Variant 19-32881854-G-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_032816.5(CEP89):c.2125C>A(p.Gln709Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000499 in 1,601,984 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CEP89
NM_032816.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.98

Variant links:

Genes affected

CEP89 (HGNC:25907): (centrosomal protein 89) Involved in non-motile cilium assembly. Acts upstream of or within cilium assembly. Located in several cellular components, including cytosol; microtubule cytoskeleton; and non-motile cilium. Part of ciliary transition fiber. [provided by Alliance of Genome Resources, Apr 2022]

CEP89 links:

Genome browser will be placed here

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=0.14430302).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CEP89	NM_032816.5 linkuse as main transcript	c.2125C>A	p.Gln709Lys	missense_variant	18/19	ENST00000305768.10
CEP89	XM_005259344.4 linkuse as main transcript	c.2053C>A	p.Gln685Lys	missense_variant	18/19
CEP89	XM_047439562.1 linkuse as main transcript	c.1384C>A	p.Gln462Lys	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP89	ENST00000305768.10 linkuse as main transcript	c.2125C>A	p.Gln709Lys	missense_variant	18/19	1	NM_032816.5	P3	Q96ST8-1
CEP89	ENST00000586984.6 linkuse as main transcript	c.*734C>A		3_prime_UTR_variant, NMD_transcript_variant	17/18	1
CEP89	ENST00000591698.5 linkuse as main transcript	c.*1459C>A		3_prime_UTR_variant, NMD_transcript_variant	17/18	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.00000422

AC:

AN:

237040

Hom.:

AF XY:

0.00

AC XY:

AN XY:

128726

show subpopulations

Gnomad AFR exome

AF:

0.0000645

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000414

AC:

AN:

1449754

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721082

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000222

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with CEP89-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 709 of the CEP89 protein (p.Gln709Lys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.016

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.0056

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.57

M_CAP

Benign

0.0094

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

MutationTaster

Benign

0.98

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.0

REVEL

Benign

0.063

Sift

Benign

0.29

Sift4G

Benign

0.20

Polyphen

0.082

Vest4

0.29

MutPred

0.23

Gain of ubiquitination at Q709 (P = 0.0101);

MVP

0.26

MPC

0.29

ClinPred

0.36

GERP RS

4.7

Varity_R

0.15

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over