14-80743239-A-G

Position:

• chr14-80743239-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152446.5(CEP128):​c.2642T>C​(p.Leu881Pro) 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: CEP128 NM_152446.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70

Genes affected

CEP128 (HGNC:20359): (centrosomal protein 128) Involved in protein localization. Located in centriole and spindle pole. Part of centriolar subdistal appendage. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35250622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP128	NM_152446.5	c.2642T>C	p.Leu881Pro	missense_variant	19/25	ENST00000555265.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP128	ENST00000555265.6	c.2642T>C	p.Leu881Pro	missense_variant	19/25	5	NM_152446.5	P2
CEP128	ENST00000281129.7	c.2642T>C	p.Leu881Pro	missense_variant	18/24	1		P2
CEP128	ENST00000554728.1	c.245T>C	p.Leu82Pro	missense_variant	3/3	2
CEP128	ENST00000554502.5	c.1718T>C	p.Leu573Pro	missense_variant, NMD_transcript_variant	8/15	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2023

The c.2642T>C (p.L881P) alteration is located in exon 18 (coding exon 17) of the CEP128 gene. This alteration results from a T to C substitution at nucleotide position 2642, causing the leucine (L) at amino acid position 881 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.062	T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;.;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Benign	0.18
Sift	Benign	0.035	D;D;D
Sift4G	Benign	0.10	T;T;D
Polyphen		0.99	D;D;.
Vest4		0.81
MutPred		0.43		Gain of glycosylation at L881 (P = 0.0073);Gain of glycosylation at L881 (P = 0.0073);.;
MVP		0.45
MPC		0.48
ClinPred		0.95	D
GERP RS		4.2
Varity_R		0.70
gMVP		0.74

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: rs1898925655; hg19: chr14-81209583;