rs201342438

Positions:

• chr15-48756370-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001194998.2(CEP152):​c.2878T>C​(p.Trp960Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00365 in 1,591,736 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (13 hom.)
• Consequence: CEP152 NM_001194998.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:4
• Conservation: PhyloP100: 6.71

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048254102).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00254 (386/152096) while in subpopulation NFE AF= 0.004 (272/67994). AF 95% confidence interval is 0.00361. There are 1 homozygotes in gnomad4. There are 172 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP152	NM_001194998.2	c.2878T>C	p.Trp960Arg	missense_variant	20/27	ENST00000380950.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP152	ENST00000380950.7	c.2878T>C	p.Trp960Arg	missense_variant	20/27	1	NM_001194998.2	A2
CEP152	ENST00000399334.7	c.2878T>C	p.Trp960Arg	missense_variant	20/26	1		P2
CEP152	ENST00000325747.9	c.2599T>C	p.Trp867Arg	missense_variant	19/25	1		A2

Frequencies

GnomAD3 genomes AF: 0.00255 AC: 387 AN: 151978 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000605

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000756

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00401

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00253 AC: 591 AN: 233654 Hom.: 1 AF XY: 0.00251 AC XY: 317 AN XY: 126338

Gnomad AFR exome AF: 0.000394

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00628

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000607

Gnomad FIN exome AF: 0.000867

Gnomad NFE exome AF: 0.00369

Gnomad OTH exome AF: 0.00236

GnomAD4 exome AF: 0.00377 AC: 5427 AN: 1439640 Hom.: 13 Cov.: 32 AF XY: 0.00368 AC XY: 2629 AN XY: 713762

Gnomad4 AFR exome AF: 0.000652

Gnomad4 AMR exome AF: 0.00276

Gnomad4 ASJ exome AF: 0.00594

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.000910

Gnomad4 NFE exome AF: 0.00433

Gnomad4 OTH exome AF: 0.00376

GnomAD4 genome AF: 0.00254 AC: 386 AN: 152096 Hom.: 1 Cov.: 32 AF XY: 0.00231 AC XY: 172 AN XY: 74340

Gnomad4 AFR AF: 0.000603

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000756

Gnomad4 NFE AF: 0.00400

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00376 Hom.: 1

Bravo AF: 0.00271

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00109 AC: 4

ESP6500EA AF: 0.00427 AC: 35

ExAC AF: 0.00243 AC: 294

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CEP152: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 13, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2023	Variant previously reported in the heterozygous state in three unrelated individuals with atrioventricular septal defects; however, these individuals did not have features of CEP125-related disorders and did not have a second variant identified in CEP152 (D'Alessandro et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25996639, 31696992, 34402213) -

Microcephaly 9, primary, autosomal recessive Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 15, 2013	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles	-	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

CEP152-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 19, 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 12, 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	Pathogenic	0.99
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.6	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-8.6	D;D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.87
MutPred		0.44		Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);.;
MVP		0.92
MPC		0.51
ClinPred		0.074	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.61

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: rs201342438; hg19: chr15-49048567; COSMIC: COSV57860954;