chr19-32879344-A-G

Position:

• chr19-32879344-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032816.5(CEP89):​c.2170T>C​(p.Ser724Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CEP89 NM_032816.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP89	NM_032816.5	c.2170T>C	p.Ser724Pro	missense_variant	19/19	ENST00000305768.10
CEP89	XM_005259344.4	c.2098T>C	p.Ser700Pro	missense_variant	19/19
CEP89	XM_047439562.1	c.1429T>C	p.Ser477Pro	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP89	ENST00000305768.10	c.2170T>C	p.Ser724Pro	missense_variant	19/19	1	NM_032816.5	P3
CEP89	ENST00000586984.6	c.*779T>C		3_prime_UTR_variant, NMD_transcript_variant	18/18	1
CEP89	ENST00000591698.5	c.*1504T>C		3_prime_UTR_variant, NMD_transcript_variant	18/18	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 724 of the CEP89 protein (p.Ser724Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CEP89-related conditions. ClinVar contains an entry for this variant (Variation ID: 1928815). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.13
Eigen_PC	Benign	-0.0097
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.60	N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.22
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.25		Loss of phosphorylation at S724 (P = 0.0474);
MVP		0.36
MPC		0.57
ClinPred		0.93	D
GERP RS		2.7
Varity_R		0.48
gMVP		0.70

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: rs1049468213; hg19: chr19-33370250;