rs2306187

Positions:

• chr15-48752341-C-G
• chr15-48752341-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001194998.2(CEP152):​c.3466+8G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,764 control chromosomes in the GnomAD database, including 28,309 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (7186 hom., cov: 32)
  • Exomes 𝑓: 0.15 (21123 hom.)
• Consequence: CEP152 NM_001194998.2 splice_region, intron
• Scores: Splicing: ADA: 0.000004609
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.533

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 15-48752341-C-G is Benign according to our data. Variant chr15-48752341-C-G is described in ClinVar as [Benign]. Clinvar id is 95653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48752341-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP152	NM_001194998.2	c.3466+8G>C		splice_region_variant, intron_variant		ENST00000380950.7	NP_001181927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP152	ENST00000380950.7	c.3466+8G>C		splice_region_variant, intron_variant		1	NM_001194998.2	ENSP00000370337.2
CEP152	ENST00000399334.7	c.3466+8G>C		splice_region_variant, intron_variant		1		ENSP00000382271.3
CEP152	ENST00000325747.9	c.3187+8G>C		splice_region_variant, intron_variant		1		ENSP00000321000.5

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38280 AN: 151916 Hom.: 7161 Cov.: 32

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.0819

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.207

GnomAD3 exomes AF: 0.194 AC: 48442 AN: 249462 Hom.: 6912 AF XY: 0.182 AC XY: 24593 AN XY: 135340

Gnomad AFR exome AF: 0.527

Gnomad AMR exome AF: 0.236

Gnomad ASJ exome AF: 0.0827

Gnomad EAS exome AF: 0.491

Gnomad SAS exome AF: 0.134

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.147 AC: 214448 AN: 1461728 Hom.: 21123 Cov.: 32 AF XY: 0.144 AC XY: 104944 AN XY: 727164

Gnomad4 AFR exome AF: 0.530

Gnomad4 AMR exome AF: 0.234

Gnomad4 ASJ exome AF: 0.0797

Gnomad4 EAS exome AF: 0.446

Gnomad4 SAS exome AF: 0.135

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.164

GnomAD4 genome AF: 0.252 AC: 38338 AN: 152036 Hom.: 7186 Cov.: 32 AF XY: 0.251 AC XY: 18665 AN XY: 74316

Gnomad4 AFR AF: 0.514

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.0819

Gnomad4 EAS AF: 0.472

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.142

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.205

Alfa AF: 0.113 Hom.: 434

Bravo AF: 0.274

Asia WGS AF: 0.296 AC: 1028 AN: 3478

EpiCase AF: 0.125

EpiControl AF: 0.123

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Microcephaly 9, primary, autosomal recessive Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Seckel syndrome 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.7
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000046
dbscSNV1_RF	Benign	0.0
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: rs2306187; hg19: chr15-49044538; COSMIC: COSV57857859;