rs182018947

Positions:

• chr15-48767448-A-C
• chr15-48767448-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001194998.2(CEP152):​c.2034T>G​(p.Tyr678*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,614,094 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: CEP152 NM_001194998.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:1
• Conservation: PhyloP100: -0.999

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]

CEP152 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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
• PP5: Variant 15-48767448-A-C is Pathogenic according to our data. Variant chr15-48767448-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 158240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48767448-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP152	NM_001194998.2	c.2034T>G	p.Tyr678*	stop_gained	16/27	ENST00000380950.7	NP_001181927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP152	ENST00000380950.7	c.2034T>G	p.Tyr678*	stop_gained	16/27	1	NM_001194998.2	ENSP00000370337.2
CEP152	ENST00000399334.7	c.2034T>G	p.Tyr678*	stop_gained	16/26	1		ENSP00000382271.3
CEP152	ENST00000325747.9	c.1755T>G	p.Tyr585*	stop_gained	15/25	1		ENSP00000321000.5

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000272 AC: 68 AN: 249546 Hom.: 0 AF XY: 0.000236 AC XY: 32 AN XY: 135384

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000334

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000267 AC: 390 AN: 1461816 Hom.: 0 Cov.: 33 AF XY: 0.000285 AC XY: 207 AN XY: 727196

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000249

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74454

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000309 Hom.: 0

Bravo AF: 0.000431

ESP6500AA AF: 0.00176 AC: 7

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.000331 AC: 40

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 9, primary, autosomal recessive Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 11, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000295, PM2). The variant was observed in trans with a pathogenic variant (NM_001194998.1:c.314G>A) as compound heterozygous (3billion dataset, PM3).The variant has been reported as pathogenic (ClinVar ID: VCV000158240.10). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 28, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Jan 28, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30833958, 31980526, 25525159, 21131973, 27219052, 34426522) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CEP152: PVS1, PM2, PM3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Tyr678*) 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 (rs182018947, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with CEP152-related conditions (PMID: 21131973). ClinVar contains an entry for this variant (Variation ID: 158240). For these reasons, this variant has been classified as Pathogenic. -

Seckel syndrome 5 Pathogenic:3 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained c.2034T>G(p.Tyr678Ter) variant in CEP152 gene has been reported previously in compound heterozygous state in individual(s) affected with Seckel syndrome (Kalay E, et. al., 2011; Fujikura K., 2016). The p.Tyr678Ter variant has been reported with allele frequency of 0.03% in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Signifiance / Likely Pathogenic / Pathogenic (multiple submissions). The nucleotide change c.2034T>G in CEP152 is predicted as conserved by GERP++. This sequence change creates a premature translational stop signal (p.Tyr678Ter) in the CEP152 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2011	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 13, 2022

The c.2034T>G (p.Y678*) alteration, located in exon 16 (coding exon 15) of the CEP152 gene, consists of a T to G substitution at nucleotide position 2034. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 678. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in the compound heterozygous state with a second CEP152 alteration in a patient with clinical features of CEP152-related Seckel syndrome (Kalay, 2011). Based on the available evidence, this alteration is classified as pathogenic. -

CEP152-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 24, 2023

- -

Seckel syndrome 5;C3553886:Microcephaly 9, primary, autosomal recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	26
DANN	Uncertain	0.99
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.18	N
Vest4		0.92
GERP RS		0.030
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: rs182018947; hg19: chr15-49059645; COSMIC: COSV57858813; COSMIC: COSV57858813;