rs267606718

chr15-48756289-G-Achr15-48756289-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001194998.2(CEP152):c.2959C>T(p.Arg987Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,576,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R987R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CEP152 NM_001194998.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.31

Genes affected

CEP152 (HGNC:29298): (centrosomal protein 152) This gene encodes a protein that is thought to be involved with centrosome function. Mutations in this gene have been associated with primary microcephaly (MCPH4). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP152	NM_001194998.2	c.2959C>T	p.Arg987Ter	stop_gained	20/27	ENST00000380950.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP152	ENST00000380950.7	c.2959C>T	p.Arg987Ter	stop_gained	20/27	1	NM_001194998.2	A2
CEP152	ENST00000399334.7	c.2959C>T	p.Arg987Ter	stop_gained	20/26	1		P2
CEP152	ENST00000325747.9	c.2680C>T	p.Arg894Ter	stop_gained	19/25	1		A2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151834 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000905 AC: 2 AN: 220876 Hom.: 0 AF XY: 0.00000835 AC XY: 1 AN XY: 119752

Gnomad AFR exome AF: 0.00

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: 0.0000501

Gnomad NFE exome AF: 0.00000953

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000105 AC: 15 AN: 1424772 Hom.: 0 Cov.: 32 AF XY: 0.00000567 AC XY: 4 AN XY: 705272

Gnomad4 AFR exome AF: 0.0000634

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000109

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151834 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74144

Gnomad4 AFR AF: 0.00

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 9, primary, autosomal recessive Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 09, 2010	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	CEP152: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 09, 2023	This sequence change creates a premature translational stop signal (p.Arg987*) in the CEP152 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP152 are known to be pathogenic (PMID: 21131973). This variant is present in population databases (rs267606718, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with CEP152-related conditions (PMID: 20598275). ClinVar contains an entry for this variant (Variation ID: 56). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	38
Dann	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.94
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs267606718; hg19: chr15-49048486; COSMIC: COSV100359016;