chr15-48793359-T-G

Position:

• chr15-48793359-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.24

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
CEP152	NM_001194998.2	c.794A>C	p.Gln265Pro	missense_variant	7/27	ENST00000380950.7	NP_001181927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP152	ENST00000380950.7	c.794A>C	p.Gln265Pro	missense_variant	7/27	1	NM_001194998.2	ENSP00000370337.2
CEP152	ENST00000399334.7	c.794A>C	p.Gln265Pro	missense_variant	7/26	1		ENSP00000382271.3
CEP152	ENST00000325747.9	c.515A>C	p.Gln172Pro	missense_variant	6/25	1		ENSP00000321000.5
CEP152	ENST00000560322.5	n.794A>C		non_coding_transcript_exon_variant	7/13	1		ENSP00000453440.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249462 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135360

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: 13 AN: 1461714 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727170

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.: 32

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 9, primary, autosomal recessive Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 24, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 09, 2010	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 03, 2022	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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2022	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) -

CEP152-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 01, 2017

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.7	M;M;.
PrimateAI	Benign	0.46	T
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	D
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

Other links and lift over

dbSNP: rs267606717; hg19: chr15-49085556;