15-48772501-T-C

Variant names:

• chr15-48772501-T-C
• rs75994436
• NM_001194998.2:c.1768A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001194998.2(CEP152):​c.1768A>G​(p.Ser590Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S590R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEP152 NM_001194998.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81
• Publications: 1 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.063705385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP152	NM_001194998.2	c.1768A>G	p.Ser590Gly	missense_variant	Exon 13 of 27	ENST00000380950.7	NP_001181927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP152	ENST00000380950.7	c.1768A>G	p.Ser590Gly	missense_variant	Exon 13 of 27	1	NM_001194998.2	ENSP00000370337.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly 9, primary, autosomal recessive Uncertain:1

Mar 04, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0082	T;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.52	T;T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.064	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.92	L;L;.
PhyloP100		2.8
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.59	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.0050	B;.;B
Vest4		0.099
MutPred		0.058		Loss of phosphorylation at S590 (P = 0.0188);Loss of phosphorylation at S590 (P = 0.0188);.;
MVP		0.82
MPC		0.077
ClinPred		0.13	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.059
gMVP		0.032

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

Other links and lift over

dbSNP: rs75994436; hg19: chr15-49064698;