chr15-48756370-A-G

Position:

chr15-48756370-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:4

Conservation

PhyloP100: 6.71

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	c.2878T>C	p.Trp960Arg	missense_variant	20/27	1	NM_001194998.2	A2	O94986-4
CEP152	ENST00000399334.7 linkuse as main transcript	c.2878T>C	p.Trp960Arg	missense_variant	20/26	1		P2	O94986-3
CEP152	ENST00000325747.9 linkuse as main transcript	c.2599T>C	p.Trp867Arg	missense_variant	19/25	1		A2	O94986-1

Frequencies

GnomAD3 genomes

AF:

0.00255

AC:

387

AN:

151978

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00251

AC XY:

317

AN XY:

126338

show subpopulations

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.:

Cov.:

AF XY:

0.00368

AC XY:

2629

AN XY:

713762

show subpopulations

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.:

Cov.:

AF XY:

0.00231

AC XY:

172

AN XY:

74340

show subpopulations

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.:

Bravo

AF:

0.00271

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00109

AC:

ESP6500EA

AF:

0.00427

AC:

ExAC

AF:

0.00243

AC:

294

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 13, 2015	- -
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) -
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 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Microcephaly 9, primary, autosomal recessive

Pathogenic:1Uncertain: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, no assertion criteria provided

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

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.74

T;T;T

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.048

T;T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.6

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.67

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over