rs181295720

chr15-48784114-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001194998.2(CEP152):c.1180A>G(p.Ile394Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,613,150 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (12 hom.)
• Consequence: CEP152 NM_001194998.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: -0.257

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050874054).
• BP6: Variant 15-48784114-T-C is Benign according to our data. Variant chr15-48784114-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158224.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=2, Benign=1}. Variant chr15-48784114-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0021 (320/152272) while in subpopulation NFE AF= 0.00316 (215/67994). AF 95% confidence interval is 0.00282. There are 0 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP152	NM_001194998.2	c.1180A>G	p.Ile394Val	missense_variant	10/27	ENST00000380950.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP152	ENST00000380950.7	c.1180A>G	p.Ile394Val	missense_variant	10/27	1	NM_001194998.2	A2
	ENST00000558304.1	n.399T>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 320 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00243 AC: 602 AN: 248000 Hom.: 3 AF XY: 0.00267 AC XY: 359 AN XY: 134552

Gnomad AFR exome AF: 0.000583

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.00659

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00161

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00345

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.00292 AC: 4268 AN: 1460878 Hom.: 12 Cov.: 31 AF XY: 0.00302 AC XY: 2194 AN XY: 726710

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00220

Gnomad4 ASJ exome AF: 0.00770

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00183

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00318

Gnomad4 OTH exome AF: 0.00343

GnomAD4 genome AF: 0.00210 AC: 320 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.00200 AC XY: 149 AN XY: 74458

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00316

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00319 Hom.: 1

Bravo AF: 0.00214

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00137 AC: 5

ESP6500EA AF: 0.00319 AC: 26

ExAC AF: 0.00221 AC: 267

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	CEP152: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2020	This variant is associated with the following publications: (PMID: 25996639) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 07, 2018	- -

Microcephaly 9, primary, autosomal recessive Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

CEP152-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 02, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Seckel syndrome 5 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	8.3
Dann	Benign	0.59
DEOGEN2	Benign	0.0037	T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0051	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.82	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.060	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.018	B;.;B
Vest4		0.10
MVP		0.52
MPC		0.055
ClinPred		0.0012	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.018

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs181295720; hg19: chr15-49076311;