rs149478199

Positions:

• chr15-48741622-G-C

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.4072C>G​(p.Gln1358Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000369 in 1,614,074 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (3 hom.)
• Consequence: CEP152 NM_001194998.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 3.91

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=0.0039657354).
• BP6: Variant 15-48741622-G-C is Benign according to our data. Variant chr15-48741622-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158262.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=4, Uncertain_significance=1}. Variant chr15-48741622-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00192 (292/152248) while in subpopulation AFR AF= 0.00662 (275/41548). AF 95% confidence interval is 0.00598. There are 1 homozygotes in gnomad4. There are 121 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP152	NM_001194998.2	c.4072C>G	p.Gln1358Glu	missense_variant	26/27	ENST00000380950.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP152	ENST00000380950.7	c.4072C>G	p.Gln1358Glu	missense_variant	26/27	1	NM_001194998.2	A2
CEP152	ENST00000399334.7	c.3904C>G	p.Gln1302Glu	missense_variant	25/26	1		P2
CEP152	ENST00000325747.9	c.3793C>G	p.Gln1265Glu	missense_variant	25/25	1		A2
CEP152	ENST00000561245.1	c.142+9C>G		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 292 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00664

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000405 AC: 101 AN: 249398 Hom.: 1 AF XY: 0.000310 AC XY: 42 AN XY: 135302

Gnomad AFR exome AF: 0.00601

Gnomad AMR exome AF: 0.000116

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: 0.000165

GnomAD4 exome AF: 0.000208 AC: 304 AN: 1461826 Hom.: 3 Cov.: 32 AF XY: 0.000182 AC XY: 132 AN XY: 727208

Gnomad4 AFR exome AF: 0.00753

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.00163 AC XY: 121 AN XY: 74444

Gnomad4 AFR AF: 0.00662

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000296 Hom.: 0

Bravo AF: 0.00195

ESP6500AA AF: 0.00483 AC: 18

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000463 AC: 56

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	CEP152: BP4 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 22, 2015	- -

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. -

CEP152-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2019

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	0.073
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.55
DEOGEN2	Benign	0.030	T;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.61	T;T;T
MetaRNN	Benign	0.0040	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.092	T;T;T
Sift4G	Benign	0.090	T;T;T
Polyphen		0.073	.;.;B
Vest4		0.15
MVP		0.47
MPC		0.068
ClinPred		0.025	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.025

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: rs149478199; hg19: chr15-49033819;