rs149176738

chr15-48767078-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_001194998.2(CEP152):c.2262G>A(p.Glu754=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,613,152 control chromosomes in the GnomAD database, including 7 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 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (7 hom.)
• Consequence: CEP152 NM_001194998.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.380

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 15-48767078-C-T is Benign according to our data. Variant chr15-48767078-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158242.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=2}. Variant chr15-48767078-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00188 (286/152272) while in subpopulation NFE AF= 0.0031 (211/68008). AF 95% confidence interval is 0.00276. There are 0 homozygotes in gnomad4. There are 142 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP152	NM_001194998.2	c.2262G>A	p.Glu754=	synonymous_variant	17/27	ENST00000380950.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP152	ENST00000380950.7	c.2262G>A	p.Glu754=	synonymous_variant	17/27	1	NM_001194998.2	A2
CEP152	ENST00000399334.7	c.2262G>A	p.Glu754=	synonymous_variant	17/26	1		P2
CEP152	ENST00000325747.9	c.1983G>A	p.Glu661=	synonymous_variant	16/25	1		A2

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00193 AC: 481 AN: 248940 Hom.: 1 AF XY: 0.00192 AC XY: 260 AN XY: 135146

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.000956

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00448

Gnomad NFE exome AF: 0.00263

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00240 AC: 3502 AN: 1460880 Hom.: 7 Cov.: 32 AF XY: 0.00233 AC XY: 1690 AN XY: 726790

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.00368

Gnomad4 NFE exome AF: 0.00271

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74470

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.00310

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00206 Hom.: 0

Bravo AF: 0.00158

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CEP152: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2021	- -

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. -

Seckel syndrome 5 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 26, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	2.4
Dann	Benign	0.48

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: rs149176738; hg19: chr15-49059275;