15-48793359-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001194998.2(CEP152):c.794A>C(p.Gln265Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

CEP152
NM_001194998.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.24

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 Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

PP5

Variant 15-48793359-T-G is Pathogenic according to our data. Variant chr15-48793359-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48793359-T-G is described in Lovd as [Pathogenic]. Variant chr15-48793359-T-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP152	NM_001194998.2 link	c.794A>C	p.Gln265Pro	missense_variant	Exon 7 of 27	ENST00000380950.7	NP_001181927.1	O94986-4Q3B7A2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CEP152	ENST00000380950.7 link	c.794A>C	p.Gln265Pro	missense_variant	Exon 7 of 27	1	NM_001194998.2	ENSP00000370337.2	O94986-4
CEP152	ENST00000399334.7 link	c.794A>C	p.Gln265Pro	missense_variant	Exon 7 of 26	1		ENSP00000382271.3	O94986-3
CEP152	ENST00000325747.9 link	c.515A>C	p.Gln172Pro	missense_variant	Exon 6 of 25	1		ENSP00000321000.5	O94986-1
CEP152	ENST00000560322.5 link	n.794A>C		non_coding_transcript_exon_variant	Exon 7 of 13	1		ENSP00000453440.1	A0A075B719

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249462

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135360

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461714

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000166

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly 9, primary, autosomal recessive

Pathogenic:2

Jul 24, 2014

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:2

May 31, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20598275, 23456457, 21668957, 30086807) -

Dec 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CEP152 protein function. ClinVar contains an entry for this variant (Variation ID: 55). This missense change has been observed in individual(s) with primary microcephaly (PMID: 20598275). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs267606717, gnomAD 0.003%). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 265 of the CEP152 protein (p.Gln265Pro). -

CEP152-related disorder

Pathogenic:1

Sep 01, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CEP152 c.794A>C (p.Gln265Pro) missense variant has been reported in one study in which it was found in three individuals with microcephaly, with head circumferences between five and seven standard deviations below the mean, including in two individuals in a homozygous state and in one individual in a compound heterozygous state with a null variant on the second allele (Guernsey et al. 2010). The p.Gln265Pro variant was found in a heterozygous state in each of the unaffected parents of the affected individuals. The p.Gln265Pro variant was absent from 496 control chromosomes including 310 local Maritime control chromosomes and 186 European control chromosomes from the Centre d'Etude du Polymorphisme Humain (CEPH) (Guernsey et al. 2010). The variant is reported at a frequency of 0.000027 in the European (non-Finnish) population of the Genome Aggregation Database. Transfection of the variant protein into human U2OS osteosarcoma-derived cells did not affect localization, with the variant protein being found in the centrosomes similarly to wild type. However, the Gln265 residue is highly conserved among vertebrates and is predicted to fall in a coiled-coiled region predicted to be disrupted by substitution of a proline residue (Guernsey et al. 2010). Based on the evidence, the c.794A>C (p.Gln265Pro) variant is classified as likely pathogenic for CEP152-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Uncertain

0.099

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.7

M;M;.

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Uncertain

0.64

Sift

Uncertain

0.0040

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.88

MVP

0.97

MPC

0.43

ClinPred

0.96

GERP RS

5.8

Varity_R

0.79

gMVP

0.68

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