rs188101277

chr15-48797497-C-T

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.344G>A(p.Arg115Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,614,096 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R115R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (21 hom.)
• Consequence: CEP152 NM_001194998.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: -1.00

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002890259).
• BP6: Variant 15-48797497-C-T is Benign according to our data. Variant chr15-48797497-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158257.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3, Benign=1}. Variant chr15-48797497-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00297 (453/152330) while in subpopulation AMR AF= 0.00438 (67/15298). AF 95% confidence interval is 0.00354. There are 1 homozygotes in gnomad4. There are 208 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP152	NM_001194998.2	c.344G>A	p.Arg115Gln	missense_variant	5/27	ENST00000380950.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP152	ENST00000380950.7	c.344G>A	p.Arg115Gln	missense_variant	5/27	1	NM_001194998.2	A2
CEP152	ENST00000399334.7	c.344G>A	p.Arg115Gln	missense_variant	5/26	1		P2
CEP152	ENST00000325747.9	c.261+164G>A		intron_variant		1		A2
CEP152	ENST00000560322.5	c.344G>A	p.Arg115Gln	missense_variant	5/13	1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00379

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00270 AC: 673 AN: 249466 Hom.: 2 AF XY: 0.00283 AC XY: 383 AN XY: 135340

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.00426

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.00356

Gnomad OTH exome AF: 0.00380

GnomAD4 exome AF: 0.00407 AC: 5952 AN: 1461766 Hom.: 21 Cov.: 32 AF XY: 0.00395 AC XY: 2871 AN XY: 727172

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00427

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00273

Gnomad4 NFE exome AF: 0.00473

Gnomad4 OTH exome AF: 0.00412

GnomAD4 genome AF: 0.00297 AC: 453 AN: 152330 Hom.: 1 Cov.: 32 AF XY: 0.00279 AC XY: 208 AN XY: 74488

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00379

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00328 Hom.: 0

Bravo AF: 0.00322

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00294 AC: 11

ESP6500EA AF: 0.00487 AC: 40

ExAC AF: 0.00240 AC: 290

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00445

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 18, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CEP152: BP4, BS2 -

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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 12, 2017

- -

CEP152-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2021

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	0.063
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.10
Dann	Benign	0.61
DEOGEN2	Benign	0.00052	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.2	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.66	N;N
REVEL	Benign	0.011
Sift	Benign	0.67	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.0050	B;.
Vest4		0.14
MVP		0.25
MPC		0.072
ClinPred		0.00027	T
GERP RS		-6.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.012
gMVP		0.052

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: rs188101277; hg19: chr15-49089694;