3-134495343-T-C

Position:

• chr3-134495343-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001353108.3(CEP63):​c.23T>C​(p.Ile8Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEP63 NM_001353108.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70

Genes affected

CEP63 (HGNC:25815): (centrosomal protein 63) This gene encodes a protein with six coiled-coil domains. The protein is localized to the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells. Several alternatively spliced transcript variants have been found, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

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=0.22911522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP63	NM_001353108.3	c.23T>C	p.Ile8Thr	missense_variant	2/15	ENST00000675561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP63	ENST00000675561.1	c.23T>C	p.Ile8Thr	missense_variant	2/15		NM_001353108.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Invitae

Oct 13, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 8 of the CEP63 protein (p.Ile8Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CEP63-related conditions. ClinVar contains an entry for this variant (Variation ID: 1506610). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CEP63 protein function. 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	0.65
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	.;.;T;.;.;T;T;T;T
Eigen	Benign	-0.0022
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D;.;D;D;D;T;.;.;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.88	N;N;N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.1	N;N;N;.;N;N;N;.;N
REVEL	Benign	0.088
Sift	Uncertain	0.0040	D;D;D;.;D;D;D;.;D
Sift4G	Uncertain	0.024	D;D;D;D;D;D;D;D;D
Polyphen		0.039	B;B;.;B;B;.;B;B;B
Vest4		0.35
MutPred		0.31		Gain of disorder (P = 0.0186);Gain of disorder (P = 0.0186);Gain of disorder (P = 0.0186);Gain of disorder (P = 0.0186);Gain of disorder (P = 0.0186);Gain of disorder (P = 0.0186);Gain of disorder (P = 0.0186);Gain of disorder (P = 0.0186);Gain of disorder (P = 0.0186);
MVP		0.60
MPC		0.047
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.12
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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.

Other links and lift over

hg19: chr3-134214185;