Genetic Variant CEP152:p.Val517Ile (chr15-48781224-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001194998.2(CEP152):c.1549G>A(p.Val517Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V517L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CEP152
NM_001194998.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.361

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

microcephaly with or without short stature
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Seckel syndrome 5
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
microcephaly 9, primary, autosomal recessive
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autosomal recessive primary microcephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Seckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CEP152 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08195707).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001194998.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP152	NM_001194998.2	MANE Select	c.1549G>A	p.Val517Ile	missense	Exon 12 of 27	NP_001181927.1
	CEP152	NM_014985.4		c.1549G>A	p.Val517Ile	missense	Exon 12 of 26	NP_055800.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEP152	ENST00000380950.7	TSL:1 MANE Select	c.1549G>A	p.Val517Ile	missense	Exon 12 of 27	ENSP00000370337.2
CEP152	ENST00000399334.7	TSL:1	c.1549G>A	p.Val517Ile	missense	Exon 12 of 26	ENSP00000382271.3
CEP152	ENST00000325747.9	TSL:1	c.1270G>A	p.Val424Ile	missense	Exon 11 of 25	ENSP00000321000.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461228

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726946

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39556

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111672

Other (OTH)

AF:

0.00

AC:

AN:

60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0033

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.71

M_CAP

Benign

0.023

MetaRNN

Benign

0.082

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.9

PhyloP100

0.36

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.36

REVEL

Benign

0.092

Sift

Benign

0.30

Sift4G

Benign

0.40

Polyphen

0.015

Vest4

0.23

MutPred

0.18

Loss of MoRF binding (P = 0.1345)

MVP

0.83

MPC

0.056

ClinPred

0.091

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.044

gMVP

0.054

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over