20-35462506-G-A

Position:

• chr20-35462506-G-A

Variant summary

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

The NM_007186.6(CEP250):​c.139G>A​(p.Glu47Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CEP250 NM_007186.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.00

Genes affected

CEP250 (HGNC:1859): (centrosomal protein 250) This gene encodes a core centrosomal protein required for centriole-centriole cohesion during interphase of the cell cycle. The encoded protein dissociates from the centrosomes when parental centrioles separate at the beginning of mitosis. The protein associates with and is phosphorylated by NIMA-related kinase 2, which is also associated with the centrosome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

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	Protein	UniProt
CEP250	NM_007186.6	c.139G>A	p.Glu47Lys	missense_variant	4/35	ENST00000397527.6	NP_009117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP250	ENST00000397527.6	c.139G>A	p.Glu47Lys	missense_variant	4/35	5	NM_007186.6	ENSP00000380661.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457786 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724830

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 47 of the CEP250 protein (p.Glu47Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CEP250-related conditions. ClinVar contains an entry for this variant (Variation ID: 1471060). 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	Benign	0.24
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T;T;T;T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.63	D;D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.5	.;.;M;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0080	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;.;D;.;.
Vest4		0.44, 0.59
MutPred		0.48		Loss of ubiquitination at K43 (P = 0.0219);Loss of ubiquitination at K43 (P = 0.0219);Loss of ubiquitination at K43 (P = 0.0219);Loss of ubiquitination at K43 (P = 0.0219);Loss of ubiquitination at K43 (P = 0.0219);
MVP		0.68
MPC		0.55
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.57
gMVP		0.43

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: rs2062777969; hg19: chr20-34050331; COSMIC: COSV61169183; COSMIC: COSV61169183;